65 results on '"Kronenberg, Mitchell"'
Search Results
2. When Less Is More: T Lymphocyte Populations with Restricted Antigen Receptor Diversity.
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Kronenberg, Mitchell
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T cells , *CYTOLOGICAL research , *POLYMERASE chain reaction , *IMMUNE system , *GEL electrophoresis , *LYMPHOCYTES - Abstract
The article reports on findings of two research papers including one on T lymphocyte with restricted antigen receptor diversity by Masaru Taniguchi & others, and another on human cells by Steven Balk & colleagues. Topics include the effects of invariant natural killer T cells on immune system, use of denaturing gel electrophoresis, polymerase chain reaction, and cloning for sequencing two invariant T-cell receptor (TCR) rearrangements & discovery of lymphocytes with restricted TCR diversity.
- Published
- 2014
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3. Antigen-Dependent versus -Independent Activation of Invariant NKT Cells during Infection.
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Holzapfel, Keli L., Tyznik, Aaron J., Kronenberg, Mitchell, and Hogquist, Kristin A.
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B cell receptors , *CELLULAR signal transduction , *GREEN fluorescent protein , *TRANSGENIC mice , *CYTOKINES , *SALMONELLA typhimurium , *KILLER cells , *INTERFERON gamma - Abstract
CD1d-reactive invariant NKT cells (iNKT) play a vital role in determining the characteristics of immune responses to infectious agents. Previous reports suggest that iNKT cell activation during infection can be: 1) solely driven by cytokines from innate immune cells, 2) require microbial Ag, or 3) require self-Ag. In this study, we examined the role of Ag receptor stimulation in iNKT cells during several bacterial and viral infections. To test for Ag receptor signaling, Nur77gfp BAC transgenic mice, which upregulate GFP in response to Ag receptor but not inflammatory signals, were analyzed. iNKT cells in the reporter mice infected with mouse CMV produced IFN-γ but did not upregulate GFP, consistent with their reported CD1d-independent activation. However, two bacteria known to produce lipid Ags for iNKT cells induced GFP expression and cytokine production. In contrast, although Salmonella typhimurium was proposed to induce the presentation of a self-lipid, iNKT cells produced IFN-γ but did not upregulate GFP postinfection in vivo. Even in CD1d-deficient hosts, iNKT cells were still able to produce IFN-γ after S. typhimurium infection. Furthermore, although it has been proposed that endogenous lipid presentation is a result of TLR stimulation of APCs, injection of different TLR agonists led to iNKT cell IFN-γ but not increased GFP expression. These data indicate that robust iNKT cell responses to bacteria, as well as viruses, can be obtained in the absence of antigenic stimulation. [ABSTRACT FROM AUTHOR]
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- 2014
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- View/download PDF
4. Kimishige Ishizaka, M.D., Ph.D. (AAI '58), December 3, 1925 to July 6, 2018.
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Kirchweger, Gina, Lamar, Elise, and Kronenberg, Mitchell
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IMMUNOLOGISTS - Published
- 2018
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5. The Protein Phosphatase Shp1 Regulates Invariant NKT Cell Effector Differentiation Independently of TCR and Slam Signaling.
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Tleugabulova, Mayra Cruz, Zhao, Meng, Lau, Irene, Kuypers, Meggie, Wirianto, Clarissa, Umanã, Juan Mauricio, Lin, Qiaochu, Kronenberg, Mitchell, and Mallevaey, Thierry
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PHOSPHOPROTEIN phosphatases , *CELL differentiation , *MITOGEN-activated protein kinase phosphatases , *PROTEIN-tyrosine phosphatase , *T cells , *CELL proliferation - Abstract
Invariant NKT (iNKT) cells are innate lipid-reactive T cells that develop and differentiate in the thymus into iNKT1/2/17 subsets, akin to TH1/2/17 conventional CD4 T cell subsets. The factors driving the central priming of iNKT cells remain obscure, although strong/prolonged TCR signals appear to favor iNKT2 cell development. The Src homology 2 domain--containing phosphatase 1 (Shp1) is a protein tyrosine phosphatase that has been identified as a negative regulator of TCR signaling. In this study, we found that mice with a T cell--specific deletion of Shp1 had normal iNKT cell numbers and peripheral distribution. However, iNKT cell differentiation was biased toward the iNKT2/17 subsets in the thymus but not in peripheral tissues. Shp1-deficient iNKT cells were also functionally biased toward the production of TH2 cytokines, such as IL-4 and IL-13. Surprisingly, we found no evidence that Shp1 regulates the TCR and Slamf6 signaling cascades, which have been suggested to promote iNKT2 differentiation. Rather, Shp1 dampened iNKT cell proliferation in response to IL-2, IL-7, and IL-15 but not following TCR engagement. Our findings suggest that Shp1 controls iNKT cell effector differentiation independently of positive selection through the modulation of cytokine responsiveness. [ABSTRACT FROM AUTHOR]
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- 2019
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6. Development of Asthma in Inner-City Children: Possible Roles of MAIT Cells and Variation in the Home Environment.
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Chandra, Shilpi, Wingender, Gerhard, Greenbaum, Jason A., Khurana, Archana, Gholami, Amin M., Ganesan, Anusha-Preethi, Rosenbach, Michael, Jaffee, Katy, Gern, James E., Wood, Robert, O'Connor, George, Sandel, Megan, Kattan, Meyer, Bacharier, Leonard, Togias, Alkis, Horner, Anthony A., and Kronenberg, Mitchell
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ASTHMA in children , *T cells , *ASTHMA -- Immunological aspects , *KILLER cells , *INTERFERON gamma , *ANTIGEN analysis , *PHYSIOLOGICAL effects of dust , *INDOOR air pollution , *PREVENTION , *PHYSIOLOGY - Abstract
Humans have populations of innate-like T lymphocytes with an invariant TCR a-chain that recognize nonpeptide Ags, including invariant NKT (iNKT) cells and mucosal-associated invariant T (MAIT) cells. iNKT cell involvement in human asthma is controversial, whereas there has been little analysis of MAIT cells. Using peripheral blood cells from 110 participants from the Urban Environment and Childhood Asthma (URECA) birth cohort study, these cells were analyzed for number and function. We determined whether iNKT cell or MAIT cell frequency at 1 y is correlated with the cytokine polarization of mainstream CD4+ T cells and/or the development of asthma by age 7 y. Dust samples from 300 houses were tested for iNKT cell antigenic activity. Our results show that a higher MAIT cell frequency at 1 y of age was associated with a decreased risk of asthma by age 7 y. The frequency of MAIT cells was associated with increased production of IFN-γ by activated CD4+ T cells from the URECA cohort. iNKT cell antigenic activity in bedroom dust samples was associated with higher endotoxin concentration and also with reduced risk of asthma. In conclusion, MAIT cell frequency at 1 y may reflect the tendency of the immune system toward Th1 responses and is associated with protection from asthma. Additionally, iNKT cell antigenic activity may be a marker of houses with increased microbial exposures and therefore also with protection from asthma. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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7. Selective Conditions Are Required for the Induction of Invariant NKT Cell Hyporesponsiveness by Antigenic Stimulation.
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Wingender, Gerhard, Birkholz, Alysia M., Sag, Duygu, Farber, Elisa, Chitale, Sampada, Howell, Amy R., and Kronenberg, Mitchell
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EPITOPES , *CYTOLOGICAL research , *GALACTOSYLCERAMIDES , *CYTOKINES , *ANTIGENS - Abstract
Activation of invariant (i)NKT cells with the model Ag a-galactosylceramide induces rapid production of multiple cytokines, impacting a wide variety of different immune reactions. In contrast, following secondary activation with a-galactosylceramide, the behavior of /NKT cells is altered for months, with the production of most cytokines being strongly reduced. The requirements for the induction of this hyporesponsive state, however, remain poorly defined. In this study, we show that Th 1-biasing /NKT cell Ags could induce /NKT cell hyporesponsiveness, as long as a minimum antigenic affinity was reached. In contrast, the Th2-biasing Ag OCH did not induce a hyporesponsive state, nor did cytokine-driven /NKT cell activation by LPS or infections. Furthermore, although dendritic cells and B cells have been reported to be essential for /NKT cell stimulation, neither dendritic cells nor B cells were required to induce /NKT cell hyporesponsiveness. Therefore, our data indicate that whereas some bone marrow-derived cells could induce /NKT cell hyporesponsiveness, selective conditions, dependent on the structure and potency of the Ag, were required to induce hyporesponsiveness. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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8. A Novel Glycolipid Antigen for NKT Cells That Preferentially Induces IFN-γ Production.
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Birkholz, Alysia M., Girardi, Enrico, Wingender, Gerhard, Khurana, Archana, Jing Wang, Meng Zhao, Zahner, Sonja, Illarionov, Petr A., Xiangshu Wen, Michelle Li, Weiming Yuan, Porcelli, Steven A., Besra, Gurdyal S., Zajonc, Dirk M., and Kronenberg, Mitchell
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INTERFERON gamma , *KILLER cells , *DENDRITIC cells , *GLYCOSPHINGOLIPIDS , *IMMUNOREGULATION , *CD1 antigen - Abstract
In this article, we characterize a novel Ag for invariant NKT (iNKT) cells capable of producing an especially robust Th1 response. This glycosphingolipid, DB06-1, is similar in chemical structure to the well-studied a-galactosylceramide (aGalCer), with the only change being a single atom: the substitution of a carbonyl oxygen with a sulfur atom. Although DB06-1 is not a more effective Ag in vitro, the small chemical change has a marked impact on the ability of this lipid Ag to stimulate iNKT cells in vivo, with increased IFN-γ production at 24 h compared with aGalCer, increased IL-12, and increased activation of NK cells to produce IFN-γ. These changes are correlated with an enhanced ability of DB06-1 to load in the CD1d molecules expressed by dendritic cells in vivo. Moreover, structural studies suggest a tighter fit into the CD1d binding groove by DB06-1 compared with aGalCer. Surprisingly, when iNKT cells previously exposed to DB06-1 are restimulated weeks later, they have greatly increased IL-10 production. Therefore, our data are consistent with a model whereby augmented and or prolonged presentation of a glycolipid Ag leads to increased activation of NK cells and a Th1-skewed immune response, which may result, in part, from enhanced loading into CD1d. Furthermore, our data suggest that strong antigenic stimulation in vivo may lead to the expansion of IL-10-producing iNKT cells, which could counteract the benefits of increased early IFN-γ production. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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9. Invariant NKT Cells Require Autophagy To Coordinate Proliferation and Survival Signals during Differentiation.
- Author
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Bo Pei, Meng Zhao, Miller, Brian C., Véla, Jose Luis, Bruinsma, Monique W., Virgin, Herbert W., and Kronenberg, Mitchell
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CELL differentiation , *KILLER cells , *IMMUNE system , *AUTOPHAGY , *LYMPHOCYTES , *CELL cycle - Abstract
Autophagy regulates cell differentiation, proliferation, and survival in multiple cell types, including cells of the immune system. In this study, we examined the effects of a disruption of autophagy on the differentiation of invariant NKT (iNKT) cells. Using mice with a T lymphocyte-specific deletion of Atg5 or Atg7, two members of the macroautophagic pathway, we observed a profound decrease in the iNKT cell population. The deficit is cell-autonomous, and it acts predominantly to reduce the number of mature cells, as well as the function of peripheral iNKT cells. In the absence of autophagy, there is reduced progression of iNKT cells in the thymus through the cell cycle, as well as increased apoptosis of these cells. Importantly, the reduction in Th1-biased iNKT cells is most pronounced, leading to a selective reduction in iNKT cell-derived IFN-γ. Our findings highlight the unique metabolic and genetic requirements for the differentiation of iNKT cells. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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10. Distinct Requirements for Activation of NKT and NK Cells during Viral Infection.
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Tyznik, Aaron J., Verma, Shilpi, Qiao Wang, Kronenberg, Mitchell, and Benedict, Chris A.
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KILLER cells , *ANIMAL models in research , *T cells , *DENDRITIC cells , *CYTOKINES , *GENE expression - Abstract
NK cells are key regulators of innate defense against mouse CMV (MCMV). Like NK cells, NKT cells also produce high levels of IFN-g rapidly after MCMV infection. However, whether similar mechanisms govern activation of these two cell types, as well as the significance of NKT cells for host resistance, remain unknown. In this article, we show that, although both NKT and NK cells are activated via cytokines, their particular cytokine requirements differ significantly in vitro and in vivo. IL-12 is required for NKT cell activation in vitro but is not sufficient, whereas NK cells have the capacity to be activated more promiscuously in response to individual cytokines from innate cells. In line with these results, GM-CSF-derived dendritic cells activated only NK cells upon MCMV infection, consistent with their virtual lack of IL-12 production, whereas Flt3 ligand-derived dendritic cells produced IL-12 and activated both NK and NKT cells. In vivo, NKT cell activation was abolished in IL-12-/- mice infected with MCMV, whereas NK cells were still activated. In turn, splenic NK cell activation was more IL-18 dependent. The differential requirements for IL-12 and IL-18 correlated with the levels of cytokine receptor expression by NK and NKT cells. Finally, mice lacking NKT cells showed reduced control of MCMV, and depleting NK cells further enhanced viral replication. Taken together, our results show that NKT and NK cells have differing requirements for cytokine-mediated activation, and both can contribute nonredundantly to MCMV defense, revealing that these two innate lymphocyte subsets function together to fine-tune antiviral responses. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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11. Exosome-like Nanoparticles from Intestinal Mucosal Cells Carry Prostaglandin E2 and Suppress Activation of Liver NKT Cells.
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Zhong-Bin Deng, Xiaoying Zhuang, Songwen Ju, Xiaoyu Xiang, Jingyao Mu, Yuelong Liu, Hong Jiang, Lifeng Zhang, Mobley, James, McClain, Craig, Wenke Feng, Grizzle, William, Jun Yan, Miller, Donald, Kronenberg, Mitchell, and Huang-Ge Zhang
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INTESTINAL mucosa physiology , *EXOSOMES , *DINOPROSTONE , *PHYSIOLOGICAL effects of nanoparticles , *IMMUNOSUPPRESSION , *KILLER cells , *T cells , *LIVER disease treatment - Abstract
Regulation and induction of anergy in NKT cells of the liver can inhibit autoimmune and antitumor responses by mechanisms that are poorly understood. We investigated the effects of PGE2, delivered by intestinal, mucus-derived, exosome-like nanoparticles (IDENs), on NKT cells in mice. In this study, we demonstrate that IDENs migrate to the liver where they induce NKT cell anergy. These effects were mediated by an IDENs' PGE2. Blocking PGE2 synthesis attenuated IDENs inhibition of induction of IFN-γ and IL-4 by α-galactosylceramide (α-GalCer)-stimulated liver NKT cells in a PGE2 E-type prostanoid 2/E-type prostanoid 4 receptor- mediated manner. Proinflammatory conditions enhanced the migration of IDENs to the liver where α-GalCer and PGE2 induced NKT anergy in response to subsequent α-GalCer stimulation. These findings demonstrate that IDENs carrying PGE2 can be transferred from the intestine to the liver, where they act as immune modulators, inducing an anergic-like state of NKT cells. These reagents might be developed as therapeutics for autoimmune liver diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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12. A Novel Role for IL-27 in Mediating the Survival of Activated Mouse CD4 T Lymphocytes.
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Gisen Kim, Shinnakasu, Ryo, Saris, Christiaan J. M., Cheroutre, Hilde, and Kronenberg, Mitchell
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INTERLEUKIN-27 , *LABORATORY mice , *CD4 antigen , *T cells , *CYTOKINES , *CELL proliferation , *HOMEOSTASIS - Abstract
IL-27, an IL-12 family cytokine, has pleiotropic functions in the differentiation and expansion of CD4+ T cell subsets. In this study, we discovered a novel function of IL-27. CD4+CD45RBhigh T cells from mice deficient for the a-chain of IL-27 receptor failed to induce colitis in Rag-/- recipients, because of an inability of activated donor cells to survive. Interestingly, IL-27 was indispens-able for the prevention of colitis by regulatory T cells, also because of a defect in long-term cell survival. IL-27 affected the survival of activated T lymphocytes, rather than promoting cell proliferation, by inhibiting Fas-mediated activation-induced T cell death, acting through the STAT3 signaling pathway. The addition of IL-27 during activation resulted in an increased cell number, which was correlated with decreased activation of both caspases 3 and 8. This prosurvival effect was attributed to downregulation of FasL and to the induction of the antiapoptotic protein cFLIP. Although activation induced cell death is an important mech-anism for the maintenance of immunological homeostasis, protection of lymphocytes from excessive cell death is essential for effective immunity. Our data indicate that IL-27 has a crucial role in the inhibition of activation-induced cell death, thereby permitting Ag-driven T cell expansion. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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13. ATP-Binding Cassette Transporter Gl Intrinsically Regulates Invariant NKT Cell Development.
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Sag, Duygu, Wingender, Gerhard, Nowyhed, Heba, Wu, Runpei, Gebre, Abraham K., Parks, John S., Kronenberg, Mitchell, and Hedrick, Catherine C.
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ATP-binding cassette transporters , *KILLER cells , *CELL growth , *CHOLESTEROL , *CELL populations , *LIPID rafts - Abstract
ATP-binding cassette transporter Gl (ABCG1) plays a role in the intracellular transport of cholesterol. Invariant NKT (iNKT) cells are a subpopulation of T lymphocytes that recognize glycolipid Ags. In this study, we demonstrate that ABCG1 regulates iNKT cell development and functions in a cell-intrinsic manner. Abcgl-/- mice displayed reduced frequencies of iNKT cells in thymus and periphery. Thymic j'NKT cells deficient in ABCG1 had reduced membrane lipid raft content, and showed impaired proliferation and defective maturation during the early stages of development. Moreover, we found that Abcgl-/- mice possess a higher frequency of Vß7+ iNKT cells, suggesting alterations in /NKT cell thymic selection. Furthermore, in response to CD3e/CD28 stimulation, Abcgl-/- thymic /NKT cells showed reduced production of IL-4 but increased production of IFN-7. Our results demonstrate that changes in intracellular cholesterol homeostasis by ABCG1 profoundly impact iNKT cell development and function [ABSTRACT FROM AUTHOR]
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- 2012
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14. Neutrophilic Granulocytes Modulate Invariant NKT Cell Function in Mice and Humans.
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Wingender, Gerhard, Hiss, Marcus, Engel, Isaac, Peukert, Konrad, Ley, Klaus, Haller, Hermann, Kronenberg, Mitchell, and Vietinghoff, Sibylle von
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GRANULOCYTES , *NEUTROPHILS , *CELL physiology , *KILLER cells , *TRANSCRIPTION factors , *LABORATORY mice - Abstract
Invariant NKT (iNKT) cells are a conserved &agr;&bgr;TCR+ T cell population that can swiftly produce large amounts of cytokines, thereby activating other leukocytes, including neutrophilic granulocytes (neutrophils). In this study, we investigated the reverse relationship, showing that high neutrophil concentrations suppress the iNKT cell response in mice and humans. Peripheral V&agr;14 iNKT cells from spontaneously neutrophilic mice produced reduced cytokines in response to the model iNKT cell Ag &agr;-galactosyl ceramide and expressed lower amounts of the T-box transcription factor 21 and GATA3 transcription factor than did wild-type controls. This influence was extrinsic, as iNKT cell transcription factor expression in mixed chimeric mice depended on neutrophil count, not iNKT cell genotype. Transcription factor expression was also decreased in primary iNKT cells from the neutrophil-rich bone marrow compared with spleen in wild-type mice. In vitro, the function of both mouse and human iNKT cells was inhibited by coincubation with neutrophils. This required cell-cell contact with live neutrophils. Neutrophilic inflammation in experimental peritonitis in mice decreased iNKT cell T-box transcription factor 21 and GATA3 expression and a-galactosyl ceramide-induced cytokine production in vivo. This was reverted by blockade of neutrophil mobilization. Similarly, iNKT cells from the human [ABSTRACT FROM AUTHOR]
- Published
- 2012
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15. Hepatic Stellate Cells Function as Regulatory Bystanders.
- Author
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Ichikawa, Shintaro, Mucida, Daniel, Tyznik, Aaron J., Kronenberg, Mitchell, and Cheroutre, Hilde
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T cells , *VITAMIN A , *METABOLITES , *TRETINOIN , *DENDRITIC cells - Abstract
Regulatory T cells (Tregs) contribute significantly to the tolerogenic nature of the liver. The mechanisms, however, underlying liver-associated Treg induction are still elusive. We recently identified the vitamin A metabolite, retinoic acid (RA), as a key controller that promotes TGF-ß-dependent Foxp3+ Treg induction but inhibits TGF-ß-driven Th17 differentiation. To investigate whether the RA producing hepatic stellate cells (HSC) are part of the liver tolerance mechanism, we investigated the ability of HSC to function as regulatory APC. Different from previous reports, we found that highly purified HSC did not express costimulatory molecules and only upregulated MHC class II after in vitro culture in the presence of exogenous IFN-γ. Consistent with an insufficient APC function, HSC failed to stimulate naive OT-II TCR transgenic CD4+T cells and only moderately stimulated α-galactosylceramide-primed invariant NKT cells. In contrast, HSC functioned as regulatory bystanders and promoted enhanced Foxp3 induction by OT-II TCR transgenic T cells primed by spleen dendritic cells, whereas they greatly inhibited the Th17 differentiation. Furthermore, the regulatory bystander capacity of the HSC was completely dependent on their ability to produce RA. Our data thus suggest that HSC can function as regulatory bystanders, and therefore, by promoting Tregs and suppressing Th17 differentiation, they might represent key players in the mechanism that drives liver-induced tolerance. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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16. Diverse Endogenous Antigens for Mouse NKT Cells: Self-Antigens That Are Not Glycosphingolipids.
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Pei, Bo, Speak, Anneliese O., Shepherd, Dawn, Butters, Terry, Cerundolo, Vincenzo, Platt, Frances M., and Kronenberg, Mitchell
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T cell receptors , *IMMUNE response , *GLYCOSPHINGOLIPIDS , *AUTOIMMUNITY , *MACROPHAGE activation , *ENDOSOMES , *LABORATORY mice - Abstract
NKT cells with an invariant Ag receptor (iNKT cells) represent a highly conserved and unique subset of T lymphocytes having properties of innate and adaptive immune cells. They have been reported to regulate a variety of immune responses, including the response to cancers and the development of autoimmunity. The development and activation of iNKT cells is dependent on self-Ags presented by the CD1d Ag-presenting molecule. It is widely believed that these self-Ags are glycosphingolipids (GSLs), molecules that contain ceramide as the lipid backbone. In this study, we used a variety of methods to show that mammalian Ags for mouse iNKT cells need not be GSLs, including the use of cell lines deficient in GSL biosynthesis and an inhibitor of GSL biosynthesis. Presentation of these Ags required the expression of CD1d molecules that could traffic to late endosomes, the site where self-Ag is acquired. Extracts of APCs contain a self-Ag that could stimulate iNKT cells when added to plates coated with soluble, rCD1d molecules. The Ag(s) in these extracts are resistant to sphingolipid-specific hydrolase digestion, consistent with the results using live APCs. Lyosphosphatidylcholine, a potential self-Ag that activated human iNKT cell lines, did not activate mouse iNKT cell hybridomas. Our data indicate that there may be more than one type of self-Ag for iNKT cells, that the self-Ags comparing mouse and human may not be conserved, and that the search to identify these molecules should not be confined to GSLs. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
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17. Thymus-Derived CD4 + CD8 + Cells Reside in Mediastinal Adipose Tissue and the Aortic Arch.
- Author
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Winkels H, Ghosheh Y, Kobiyama K, Kiosses WB, Orecchioni M, Ehinger E, Suryawanshi V, Herrera-De La Mata S, Marchovecchio P, Riffelmacher T, Thiault N, Kronenberg M, Wolf D, Seumois G, Vijayanand P, and Ley K
- Subjects
- Animals, DNA-Binding Proteins genetics, DNA-Binding Proteins immunology, Female, Mice, Mice, Inbred C57BL, Mice, Knockout, Natural Killer T-Cells immunology, Adipose Tissue immunology, Aorta, Thoracic immunology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Thymus Gland immunology
- Abstract
Double-positive CD4
+ CD8αβ+ (DP) cells are thought to reside as T cell progenitors exclusively within the thymus. We recently discovered an unexpected CD4+ and CD8αβ+ immune cell population in healthy and atherosclerotic mice by single-cell RNA sequencing. Transcriptomically, these cells resembled thymic DPs. Flow cytometry and three-dimensional whole-mount imaging confirmed DPs in thymus, mediastinal adipose tissue, and aortic adventitia, but nowhere else. Deep transcriptional profiling revealed differences between DP cells isolated from the three locations. All DPs were dependent on RAG2 expression and the presence of the thymus. Mediastinal adipose tissue DPs resided in close vicinity to invariant NKT cells, which they could activate in vitro. Thymus transplantation failed to reconstitute extrathymic DPs, and frequencies of extrathymic DPs were unaltered by pharmacologic inhibition of S1P1, suggesting that their migration may be locally confined. Our results define two new, transcriptionally distinct subsets of extrathymic DPs that may play a role in aortic vascular homeostasis., (Copyright © 2021 by The American Association of Immunologists, Inc.)- Published
- 2021
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18. The Protein Phosphatase Shp1 Regulates Invariant NKT Cell Effector Differentiation Independently of TCR and Slam Signaling.
- Author
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Cruz Tleugabulova M, Zhao M, Lau I, Kuypers M, Wirianto C, Umaña JM, Lin Q, Kronenberg M, and Mallevaey T
- Subjects
- Animals, Cell Differentiation genetics, Cytokines genetics, Cytokines immunology, Mice, Mice, Knockout, Natural Killer T-Cells cytology, Protein Tyrosine Phosphatase, Non-Receptor Type 6 genetics, Receptors, Antigen, T-Cell genetics, Signal Transduction genetics, Signaling Lymphocytic Activation Molecule Family Member 1 genetics, Cell Differentiation immunology, Natural Killer T-Cells immunology, Protein Tyrosine Phosphatase, Non-Receptor Type 6 immunology, Receptors, Antigen, T-Cell immunology, Signal Transduction immunology, Signaling Lymphocytic Activation Molecule Family Member 1 immunology
- Abstract
Invariant NKT (iNKT) cells are innate lipid-reactive T cells that develop and differentiate in the thymus into iNKT1/2/17 subsets, akin to T
H 1/2/17 conventional CD4 T cell subsets. The factors driving the central priming of iNKT cells remain obscure, although strong/prolonged TCR signals appear to favor iNKT2 cell development. The Src homology 2 domain-containing phosphatase 1 (Shp1) is a protein tyrosine phosphatase that has been identified as a negative regulator of TCR signaling. In this study, we found that mice with a T cell-specific deletion of Shp1 had normal iNKT cell numbers and peripheral distribution. However, iNKT cell differentiation was biased toward the iNKT2/17 subsets in the thymus but not in peripheral tissues. Shp1-deficient iNKT cells were also functionally biased toward the production of TH 2 cytokines, such as IL-4 and IL-13. Surprisingly, we found no evidence that Shp1 regulates the TCR and Slamf6 signaling cascades, which have been suggested to promote iNKT2 differentiation. Rather, Shp1 dampened iNKT cell proliferation in response to IL-2, IL-7, and IL-15 but not following TCR engagement. Our findings suggest that Shp1 controls iNKT cell effector differentiation independently of positive selection through the modulation of cytokine responsiveness., (Copyright © 2019 by The American Association of Immunologists, Inc.)- Published
- 2019
- Full Text
- View/download PDF
19. Correction: Exosome-like Nanoparticles from Intestinal Mucosal Cells Carry Prostaglandin E2 and Suppress Activation of Liver NKT Cells.
- Author
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Deng ZB, Zhuang X, Ju S, Xiang X, Mu J, Liu Y, Jiang H, Zhang L, Mobley J, McClain C, Feng W, Grizzle W, Yan J, Miller D, Kronenberg M, and Zhang HG
- Published
- 2016
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- View/download PDF
20. Invariant NKT cells require autophagy to coordinate proliferation and survival signals during differentiation.
- Author
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Pei B, Zhao M, Miller BC, Véla JL, Bruinsma MW, Virgin HW, and Kronenberg M
- Subjects
- Animals, Autophagy genetics, Autophagy-Related Protein 5, Autophagy-Related Protein 7, Cell Cycle Checkpoints genetics, Cell Differentiation genetics, Cell Differentiation immunology, Cell Survival genetics, Cytokines genetics, Cytokines metabolism, Female, Mice, Mice, Transgenic, Microtubule-Associated Proteins deficiency, Microtubule-Associated Proteins genetics, Mitochondria genetics, Mitochondria metabolism, Mutation, Natural Killer T-Cells cytology, Superoxides metabolism, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, TOR Serine-Threonine Kinases metabolism, Thymocytes cytology, Thymocytes immunology, Thymocytes metabolism, Autophagy immunology, Cell Survival immunology, Natural Killer T-Cells immunology, Natural Killer T-Cells metabolism, Signal Transduction
- Abstract
Autophagy regulates cell differentiation, proliferation, and survival in multiple cell types, including cells of the immune system. In this study, we examined the effects of a disruption of autophagy on the differentiation of invariant NKT (iNKT) cells. Using mice with a T lymphocyte-specific deletion of Atg5 or Atg7, two members of the macroautophagic pathway, we observed a profound decrease in the iNKT cell population. The deficit is cell-autonomous, and it acts predominantly to reduce the number of mature cells, as well as the function of peripheral iNKT cells. In the absence of autophagy, there is reduced progression of iNKT cells in the thymus through the cell cycle, as well as increased apoptosis of these cells. Importantly, the reduction in Th1-biased iNKT cells is most pronounced, leading to a selective reduction in iNKT cell-derived IFN-γ. Our findings highlight the unique metabolic and genetic requirements for the differentiation of iNKT cells., (Copyright © 2015 by The American Association of Immunologists, Inc.)
- Published
- 2015
- Full Text
- View/download PDF
21. Exosome-like nanoparticles from intestinal mucosal cells carry prostaglandin E2 and suppress activation of liver NKT cells.
- Author
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Deng ZB, Zhuang X, Ju S, Xiang X, Mu J, Liu Y, Jiang H, Zhang L, Mobley J, McClain C, Feng W, Grizzle W, Yan J, Miller D, Kronenberg M, and Zhang HG
- Subjects
- Animals, Clonal Anergy immunology, Cyclic AMP metabolism, Cyclic AMP-Dependent Protein Kinases metabolism, Disease Models, Animal, Exosomes immunology, Galactosylceramides immunology, Hepatitis, Autoimmune immunology, Hepatitis, Autoimmune metabolism, Humans, Intestinal Mucosa immunology, Liver metabolism, Male, Mice, Signal Transduction, Cell-Derived Microparticles metabolism, Dinoprostone metabolism, Exosomes metabolism, Intestinal Mucosa metabolism, Liver immunology, Lymphocyte Activation immunology, Natural Killer T-Cells immunology
- Abstract
Regulation and induction of anergy in NKT cells of the liver can inhibit autoimmune and antitumor responses by mechanisms that are poorly understood. We investigated the effects of PGE2, delivered by intestinal, mucus-derived, exosome-like nanoparticles (IDENs), on NKT cells in mice. In this study, we demonstrate that IDENs migrate to the liver where they induce NKT cell anergy. These effects were mediated by an IDENs' PGE2. Blocking PGE2 synthesis attenuated IDENs inhibition of induction of IFN-γ and IL-4 by α-galactosylceramide (α-GalCer)-stimulated liver NKT cells in a PGE2 E-type prostanoid 2/E-type prostanoid 4 receptor-mediated manner. Proinflammatory conditions enhanced the migration of IDENs to the liver where α-GalCer and PGE2 induced NKT anergy in response to subsequent α-GalCer stimulation. These findings demonstrate that IDENs carrying PGE2 can be transferred from the intestine to the liver, where they act as immune modulators, inducing an anergic-like state of NKT cells. These reagents might be developed as therapeutics for autoimmune liver diseases.
- Published
- 2013
- Full Text
- View/download PDF
22. A novel role for IL-27 in mediating the survival of activated mouse CD4 T lymphocytes.
- Author
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Kim G, Shinnakasu R, Saris CJ, Cheroutre H, and Kronenberg M
- Subjects
- Animals, CD4-Positive T-Lymphocytes transplantation, Cell Death genetics, Cell Death immunology, Cell Differentiation genetics, Cell Differentiation immunology, Cell Proliferation, Cell Survival genetics, Cell Survival immunology, Colitis immunology, Colitis pathology, Colitis prevention & control, Homeostasis genetics, Homeostasis immunology, Interleukins deficiency, Interleukins genetics, Lymphocyte Activation genetics, Mice, Mice, Knockout, Mice, Transgenic, Signal Transduction genetics, Signal Transduction immunology, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes immunology, Interleukins physiology, Lymphocyte Activation immunology
- Abstract
IL-27, an IL-12 family cytokine, has pleiotropic functions in the differentiation and expansion of CD4(+) T cell subsets. In this study, we discovered a novel function of IL-27. CD4(+)CD45RB(high) T cells from mice deficient for the α-chain of IL-27 receptor failed to induce colitis in Rag(-/-) recipients, because of an inability of activated donor cells to survive. Interestingly, IL-27 was indispensable for the prevention of colitis by regulatory T cells, also because of a defect in long-term cell survival. IL-27 affected the survival of activated T lymphocytes, rather than promoting cell proliferation, by inhibiting Fas-mediated activation-induced T cell death, acting through the STAT3 signaling pathway. The addition of IL-27 during activation resulted in an increased cell number, which was correlated with decreased activation of both caspases 3 and 8. This prosurvival effect was attributed to downregulation of FasL and to the induction of the antiapoptotic protein cFLIP. Although activation induced cell death is an important mechanism for the maintenance of immunological homeostasis, protection of lymphocytes from excessive cell death is essential for effective immunity. Our data indicate that IL-27 has a crucial role in the inhibition of activation-induced cell death, thereby permitting Ag-driven T cell expansion.
- Published
- 2013
- Full Text
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23. Antigen-specific cytotoxicity by invariant NKT cells in vivo is CD95/CD178-dependent and is correlated with antigenic potency.
- Author
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Wingender G, Krebs P, Beutler B, and Kronenberg M
- Subjects
- Animals, Antigens, CD1d biosynthesis, Antigens, CD1d physiology, Cell Line, Tumor, Epitopes, T-Lymphocyte toxicity, Fas Ligand Protein metabolism, Galactosylceramides toxicity, Lung Neoplasms immunology, Lung Neoplasms pathology, Lung Neoplasms therapy, Melanoma, Experimental immunology, Melanoma, Experimental pathology, Melanoma, Experimental therapy, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Natural Killer T-Cells metabolism, Natural Killer T-Cells pathology, Up-Regulation immunology, fas Receptor metabolism, Cytotoxicity Tests, Immunologic methods, Epitopes, T-Lymphocyte immunology, Fas Ligand Protein physiology, Natural Killer T-Cells immunology, fas Receptor physiology
- Abstract
Invariant NKT (iNKT) cells are a unique subset of T lymphocytes that rapidly carry out effector functions following activation with glycolipid Ags, such as the model Ag alpha-galactosylceramide. Numerous studies have investigated the mechanisms leading to Th1 and Th2 cytokine production by iNKT cells, as well as the effects of the copious amounts of cytokines these cells produce. Less is known, however, about the mechanisms of iNKT cell cytotoxicity. In this study, we investigated the effect of Ag availability and strength, as well as the molecules involved in iNKT cytotoxicity. We demonstrate that the iNKT cell cytotoxicity in vivo correlates directly with the amount of CD1d expressed by the targets as well as the TCR affinity for the target glycolipid Ag. iNKT cells from spleen, liver, and thymus were comparable in their cytotoxicity in vitro. Surprisingly, we show that the Ag-specific cytotoxicity of iNKT cells in vivo depended almost exclusively on the interaction of CD95 (Fas) with CD178 (FasL), and that this mechanism can be efficiently used for tumor protection. Therefore, unlike NK cells, which rely mostly on perforin/granzyme-mediated mechanisms, the Ag-specific cytotoxicity of iNKT cells in vivo is largely restricted to the CD95/CD178 pathway.
- Published
- 2010
- Full Text
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24. Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice.
- Author
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Barnes MJ, Aksoylar H, Krebs P, Bourdeau T, Arnold CN, Xia Y, Khovananth K, Engel I, Sovath S, Lampe K, Laws E, Saunders A, Butcher GW, Kronenberg M, Steinbrecher K, Hildeman D, Grimes HL, Beutler B, and Hoebe K
- Subjects
- Animals, B-Lymphocyte Subsets immunology, Colitis genetics, Female, GTP Phosphohydrolases genetics, GTP-Binding Proteins, Hematopoiesis genetics, Hematopoiesis immunology, Hematopoietic Stem Cells immunology, Homeostasis genetics, Homeostasis immunology, Immunoblotting, Inflammation genetics, Inflammation immunology, Intestines immunology, Intestines microbiology, Intestines pathology, Liver Diseases genetics, Liver Diseases immunology, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Self Tolerance immunology, Signal Transduction genetics, Signal Transduction immunology, T-Lymphocyte Subsets immunology, Wasting Syndrome genetics, B-Lymphocytes immunology, Colitis immunology, GTP Phosphohydrolases immunology, T-Lymphocytes immunology, Wasting Syndrome immunology
- Abstract
Homeostatic control of the immune system involves mechanisms that ensure the self-tolerance, survival and quiescence of hematopoietic-derived cells. In this study, we demonstrate that the GTPase of immunity associated protein (Gimap)5 regulates these processes in lymphocytes and hematopoietic progenitor cells. As a consequence of a recessive N-ethyl-N-nitrosourea-induced germline mutation in the P-loop of Gimap5, lymphopenia, hepatic extramedullary hematopoiesis, weight loss, and intestinal inflammation occur in homozygous mutant mice. Irradiated fetal liver chimeric mice reconstituted with Gimap5-deficient cells lose weight and become lymphopenic, demonstrating a hematopoietic cell-intrinsic function for Gimap5. Although Gimap5-deficient CD4(+) T cells and B cells appear to undergo normal development, they fail to proliferate upon Ag-receptor stimulation although NF-kappaB, MAP kinase and Akt activation occur normally. In addition, in Gimap5-deficient mice, CD4(+) T cells adopt a CD44(high)CD62L(low)CD69(low) phenotype and show reduced IL-7ralpha expression, and T-dependent and T-independent B cell responses are abrogated. Thus, Gimap5-deficiency affects a noncanonical signaling pathway required for Ag-receptor-induced proliferation and lymphocyte quiescence. Antibiotic-treatment or the adoptive transfer of Rag-sufficient splenocytes ameliorates intestinal inflammation and weight loss, suggesting that immune responses triggered by microbial flora causes the morbidity in Gimap5-deficient mice. These data establish Gimap5 as a key regulator of hematopoietic integrity and lymphocyte homeostasis.
- Published
- 2010
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25. A CD1d-dependent antagonist inhibits the activation of invariant NKT cells and prevents development of allergen-induced airway hyperreactivity.
- Author
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Lombardi V, Stock P, Singh AK, Kerzerho J, Yang W, Sullivan BA, Li X, Shiratsuchi T, Hnatiuk NE, Howell AR, Yu KO, Porcelli SA, Tsuji M, Kronenberg M, Wilson SB, and Akbari O
- Subjects
- Allergens administration & dosage, Animals, Antigens, CD1d metabolism, Binding, Competitive immunology, Cell Line, Disease Models, Animal, Female, Galactosylceramides administration & dosage, Galactosylceramides antagonists & inhibitors, Humans, Immunosuppressive Agents antagonists & inhibitors, Lymphocyte Activation drug effects, Mice, Mice, Inbred BALB C, Ovalbumin administration & dosage, Ovalbumin immunology, Phosphatidylethanolamines administration & dosage, Polyethylene Glycols administration & dosage, Allergens immunology, Antigens, CD1d physiology, Bronchial Hyperreactivity immunology, Bronchial Hyperreactivity prevention & control, Immunosuppressive Agents pharmacology, Lymphocyte Activation immunology, Natural Killer T-Cells immunology, Phosphatidylethanolamines pharmacology, Polyethylene Glycols pharmacology
- Abstract
The prevalence of asthma continues to increase in westernized countries, and optimal treatment remains a significant therapeutic challenge. Recently, CD1d-restricted invariant NKT (iNKT) cells were found to play a critical role in the induction of airway hyperreactivity (AHR) in animal models and are associated with asthma in humans. To test whether iNKT cell-targeted therapy could be used to treat allergen-induced airway disease, mice were sensitized with OVA and treated with di-palmitoyl-phosphatidyl-ethanolamine polyethylene glycol (DPPE-PEG), a CD1d-binding lipid antagonist. A single dose of DPPE-PEG prevented the development of AHR and pulmonary infiltration of lymphocytes upon OVA challenge, but had no effect on the development of OVA-specific Th2 responses. In addition, DPPE-PEG completely prevented the development of AHR after administration of alpha-galactosylceramide (alpha-GalCer) intranasally. Furthermore, we demonstrate that DPPE-PEG acts as antagonist to alpha-GalCer and competes with alpha-GalCer for binding to CD1d. Finally, we show that DPPE-PEG completely inhibits the alpha-GalCer-induced phosphorylation of ERK tyrosine kinase in iNKT cells, suggesting that DPPE-PEG specifically blocks TCR signaling and thus activation of iNKT cells. Because iNKT cells play a critical role in the development of AHR, the inhibition of iNKT activation by DPPE-PEG suggests a novel approach to treat iNKT cell-mediated diseases such as asthma.
- Published
- 2010
- Full Text
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26. Commensal microbiota and CD8+ T cells shape the formation of invariant NKT cells.
- Author
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Wei B, Wingender G, Fujiwara D, Chen DY, McPherson M, Brewer S, Borneman J, Kronenberg M, and Braun J
- Subjects
- Animals, CD8 Antigens biosynthesis, CD8-Positive T-Lymphocytes transplantation, Cell Differentiation genetics, Cell Differentiation immunology, Cytotoxicity, Immunologic genetics, Germ-Free Life immunology, Immunologic Memory genetics, Intestinal Mucosa cytology, Intestinal Mucosa immunology, Intestinal Mucosa microbiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Natural Killer T-Cells cytology, Perforin biosynthesis, Perforin deficiency, Perforin genetics, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes microbiology, Natural Killer T-Cells immunology, Natural Killer T-Cells microbiology
- Abstract
Commensal bacteria play an important role in formation of the immune system, but the mechanisms involved are incompletely understood. In this study, we analyze CD1d-restricted invariant NKT (iNKT) cells in germfree mice and in two colonies of C57BL/6 mice termed conventional flora and restricted flora (RF), stably bearing commensal microbial communities of diverse but distinct composition. In germfree mice, iNKT cells were moderately reduced, suggesting that commensal microbiota were partially required for the antigenic drive in maintaining systemic iNKT cells. Surprisingly, even greater depletion of iNKT cell population occurred in RF mice. This was in part attributable to reduced RF levels of intestinal microbial taxa (Sphingomonas spp.) known to express antigenic glycosphingolipid products. However, memory and activated CD8(+) T cells were also expanded in RF mice, prompting us to test whether CD8(+) T cell activity might be further depleting iNKT cells. Indeed, iNKT cell numbers were restored in RF mice bearing the CD8alpha(-/-) genotype or in adult wild-type RF mice acutely depleted with anti-CD8 Ab. Moreover, iNKT cells were restored in RF mice bearing the Prf1(-/-) phenotype, a key component of cytolytic function. These findings indicate that commensal microbiota, through positive (antigenic drive) and negative (cytolytic depletion by CD8(+) T cells) mechanisms, profoundly shape the iNKT cell compartment. Because individuals greatly vary in the composition of their microbial communities, enteric microbiota may play an important epigenetic role in the striking differences in iNKT cell abundance in humans and therefore in their potential contribution to host immune status.
- Published
- 2010
- Full Text
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27. Mechanisms for glycolipid antigen-driven cytokine polarization by Valpha14i NKT cells.
- Author
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Sullivan BA, Nagarajan NA, Wingender G, Wang J, Scott I, Tsuji M, Franck RW, Porcelli SA, Zajonc DM, and Kronenberg M
- Subjects
- Animals, Antigen Presentation immunology, Antigens chemistry, Antigens immunology, Antigens, CD1d chemistry, Flow Cytometry, Galactosylceramides chemistry, Glycolipids chemistry, Glycosides, Lymphocyte Activation immunology, Mice, Mice, Inbred C57BL, Monosaccharides chemistry, Signal Transduction immunology, Surface Plasmon Resonance, Transcriptional Activation, Antigens, CD1d immunology, Cytokines immunology, Galactosylceramides immunology, Glycolipids immunology, Monosaccharides immunology, Natural Killer T-Cells immunology
- Abstract
Certain glycolipid Ags for Valpha14i NKT cells can direct the overall cytokine balance of the immune response. Th2-biasing OCH has a lower TCR avidity than the most potent agonist known, alpha-galactosylceramide. Although the CD1d-exposed portions of OCH and alpha-galactosylceramide are identical, structural analysis indicates that there are subtle CD1d conformational differences due to differences in the buried lipid portion of these two Ags, likely accounting for the difference in antigenic potency. Th1-biasing C-glycoside/CD1d has even weaker TCR interactions than OCH/CD1d. Despite this, C-glycoside caused a greater downstream activation of NK cells to produce IFN-gamma, accounting for its promotion of Th1 responses. We found that this difference correlated with the finding that C-glycoside/CD1d complexes survive much longer in vivo. Therefore, we suggest that the pharmacokinetic properties of glycolipids are a major determinant of cytokine skewing, suggesting a pathway for designing therapeutic glycolipids for modulating invariant NKT cell responses.
- Published
- 2010
- Full Text
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28. T cell intrinsic heterodimeric complexes between HVEM and BTLA determine receptivity to the surrounding microenvironment.
- Author
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Cheung TC, Oborne LM, Steinberg MW, Macauley MG, Fukuyama S, Sanjo H, D'Souza C, Norris PS, Pfeffer K, Murphy KM, Kronenberg M, Spear PG, and Ware CF
- Subjects
- Animals, Flow Cytometry, Humans, Immunoprecipitation, Mice, Mice, Knockout, Receptors, Immunologic chemistry, Receptors, Immunologic metabolism, Receptors, Tumor Necrosis Factor, Member 14 chemistry, Receptors, Tumor Necrosis Factor, Member 14 metabolism, T-Lymphocytes chemistry, T-Lymphocytes metabolism, Lymphocyte Activation immunology, Receptors, Immunologic immunology, Receptors, Tumor Necrosis Factor, Member 14 immunology, Signal Transduction immunology, T-Lymphocytes immunology
- Abstract
The inhibitory cosignaling pathway formed between the TNF receptor herpesvirus entry mediator (HVEM, TNFRSF14) and the Ig superfamily members, B and T lymphocyte attenuator (BTLA) and CD160, limits the activation of T cells. However, BTLA and CD160 can also serve as activating ligands for HVEM when presented in trans by adjacent cells, thus forming a bidirectional signaling pathway. BTLA and CD160 can directly activate the HVEM-dependent NF-kappaB RelA transcriptional complex raising the question of how NF-kappaB activation is repressed in naive T cells. In this study, we show BTLA interacts with HVEM in cis, forming a heterodimeric complex in naive T cells that inhibits HVEM-dependent NF-kappaB activation. The cis-interaction between HVEM and BTLA is the predominant form expressed on the surface of naive human and mouse T cells. The BTLA ectodomain acts as a competitive inhibitor blocking BTLA and CD160 from binding in trans to HVEM and initiating NF-kappaB activation. The TNF-related ligand, LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes, or TNFSF14) binds HVEM in the cis-complex, but NF-kappaB activation was attenuated, suggesting BTLA prevents oligomerization of HVEM in the cis-complex. Genetic deletion of BTLA or pharmacologic disruption of the HVEM-BTLA cis-complex in T cells promoted HVEM activation in trans. Interestingly, herpes simplex virus envelope glycoprotein D formed a cis-complex with HVEM, yet surprisingly, promoted the activation NF-kappaB RelA. We suggest that the HVEM-BTLA cis-complex competitively inhibits HVEM activation by ligands expressed in the surrounding microenvironment, thus helping maintain T cells in the naive state.
- Published
- 2009
- Full Text
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29. NKG2A inhibits invariant NKT cell activation in hepatic injury.
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Kawamura T, Takeda K, Kaneda H, Matsumoto H, Hayakawa Y, Raulet DH, Ikarashi Y, Kronenberg M, Yagita H, Kinoshita K, Abo T, Okumura K, and Smyth MJ
- Subjects
- Animals, Antibodies, Monoclonal pharmacology, Cell Line, Chemical and Drug Induced Liver Injury metabolism, Chemical and Drug Induced Liver Injury pathology, Concanavalin A administration & dosage, Concanavalin A toxicity, Down-Regulation immunology, Growth Inhibitors biosynthesis, Growth Inhibitors genetics, Melanoma, Experimental immunology, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Knockout, NK Cell Lectin-Like Receptor Subfamily C deficiency, NK Cell Lectin-Like Receptor Subfamily C genetics, NK Cell Lectin-Like Receptor Subfamily C immunology, NK Cell Lectin-Like Receptor Subfamily D antagonists & inhibitors, NK Cell Lectin-Like Receptor Subfamily D physiology, Natural Killer T-Cells pathology, Receptors, Antigen, T-Cell physiology, Signal Transduction immunology, Chemical and Drug Induced Liver Injury immunology, Growth Inhibitors physiology, Lymphocyte Activation immunology, NK Cell Lectin-Like Receptor Subfamily C physiology, Natural Killer T-Cells immunology, Natural Killer T-Cells metabolism
- Abstract
Activation of invariant NKT (iNKT) cells in the liver is generally regarded as the critical step for Con A-induced hepatitis, and the role of NK cell receptors for iNKT cell activation is still controversial. In this study we show that blockade of the NKG2A-mediated inhibitory signal with antagonistic anti-NKG2A/C/E mAb (20d5) aggravated Con A-induced hepatitis in wild-type, Fas ligand (FasL)-mutant gld, and IL-4-deficient mice even with NK cell and CD8 T cell depletion, but not in perforin-, IFN-gamma-, or IFN-gamma- and perforin-deficient mice. Consistently, 20d5 pretreatment augmented serum IFN-gamma levels and perforin-dependent cytotoxicity of liver mononuclear cells following Con A injection, but not their FasL/Fas-dependent cytotoxicity. However, blockade of NKG2A-mediated signals during the cytotoxicity effector phase did not augment cytotoxic activity. Activated iNKT cells promptly disappeared after Con A injection, whereas NK1(-) iNKT cells, which preferentially expressed CD94/NKG2A, predominantly remained in the liver. Pretreatment with 20d5 appeared to facilitate disappearance of iNKT cells, particularly NK1(-) iNKT cells. Moreover, Con A-induced and alpha-galactosylceramide-induced hepatic injury was very severe in CD94/NKG2A-deficient DBA/2J mice compared with CD94/NKG2A-intact DBA/2JJcl mice. Overall, these results indicated that a NKG2A-mediated signal negatively regulates iNKT cell activation and hepatic injury.
- Published
- 2009
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30. Spontaneous colitis occurrence in transgenic mice with altered B7-mediated costimulation.
- Author
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Kim G, Turovskaya O, Levin M, Byrne FR, Whoriskey JS, McCabe JG, and Kronenberg M
- Subjects
- Animals, Antigens, CD genetics, Antigens, CD immunology, B7-1 Antigen genetics, CD28 Antigens genetics, CD28 Antigens immunology, CTLA-4 Antigen, Colitis genetics, Disease Models, Animal, Humans, Inflammatory Bowel Diseases genetics, Lymphocyte Activation genetics, Mice, Mice, Knockout, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins immunology, B7-1 Antigen immunology, Colitis immunology, Inflammatory Bowel Diseases immunology, T-Lymphocytes, Regulatory immunology
- Abstract
The B7 costimulatory molecules govern many aspects of T cell immune responses by interacting with CD28 for costimulation, but also with CTLA-4 for immune suppression. Although blockade of CTLA-4 with Ab in humans undergoing cancer immune therapy has led to some cases of inflammatory bowel disease, spontaneous animal models of colitis that depend upon modulation of B7 interactions have not been previously described. In this study, we demonstrate that mice expressing a soluble B7-2 Ig Fc chimeric protein spontaneously develop colitis that is dependent on CD28-mediated costimulation of CD4(+) T cells. We show that the chimeric protein has mixed agonistic/antagonist properties, and that it acts in part by blocking the cell intrinsic effects on T cell activation of engagement of CTLA-4. Disease occurred in transgenic mice that lack expression of the endogenous B7 molecules (B7 double knock-out mice), because of the relatively weak costimulatory delivered by the chimeric protein. Surprisingly, colitis was more severe in this context, which was associated with the decreased number of Foxp3(+) regulatory T cells in transgenic B7 double knock-out mice. This model provides an important tool for examining how B7 molecules and their effects on CTLA-4 modulate T cell function and the development of inflammatory diseases.
- Published
- 2008
- Full Text
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31. Cutting edge: the mechanism of invariant NKT cell responses to viral danger signals.
- Author
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Tyznik AJ, Tupin E, Nagarajan NA, Her MJ, Benedict CA, and Kronenberg M
- Subjects
- Animals, Antigen-Presenting Cells immunology, Antigen-Presenting Cells metabolism, Antigen-Presenting Cells virology, Cells, Cultured, CpG Islands immunology, Dendritic Cells immunology, Dendritic Cells metabolism, Dendritic Cells virology, Herpesviridae Infections immunology, Herpesviridae Infections virology, Immunity, Innate, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Natural Killer T-Cells metabolism, Oligodeoxyribonucleotides immunology, Toll-Like Receptor 9 physiology, Muromegalovirus immunology, Muromegalovirus pathogenicity, Natural Killer T-Cells immunology, Natural Killer T-Cells virology
- Abstract
Invariant NK T (iNKT) cells influence the response to viral infections, although the mechanisms are poorly defined. In this study we show that these innate-like lymphocytes secrete IFN-gamma upon culture with CpG oligodeoxynucleotide-stimulated dendritic cells (DCs) from mouse bone marrow. This requires TLR9 signaling and IL-12 secretion by the activated DCs, but it does not require CD1d expression. iNKT cells also produce IFN-gamma in response to mouse CMV infection. Their mechanism of mouse CMV detection is quite similar to that of CpG, requiring both TLR9 signaling and IL-12 secretion, while the need for CD1d expression is relatively minor. Consequently, iNKT cells have the ability to respond to a variety of microbes, including viruses, in an Ag-independent manner, suggesting they may play a broad role in antipathogen defenses despite their limited TCR repertoire.
- Published
- 2008
- Full Text
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32. Activation of invariant NKT cells ameliorates experimental ocular autoimmunity by a mechanism involving innate IFN-gamma production and dampening of the adaptive Th1 and Th17 responses.
- Author
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Grajewski RS, Hansen AM, Agarwal RK, Kronenberg M, Sidobre S, Su SB, Silver PB, Tsuji M, Franck RW, Lawton AP, Chan CC, and Caspi RR
- Subjects
- Animals, Autoimmune Diseases immunology, Autoimmune Diseases prevention & control, Cattle, Disease Susceptibility immunology, Eye Proteins administration & dosage, Eye Proteins immunology, Immunity, Innate, Interferon-gamma metabolism, Interferon-gamma physiology, Interleukin-17 antagonists & inhibitors, Interleukin-4 metabolism, Ligands, Mice, Mice, Inbred AKR, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred DBA, Retinol-Binding Proteins administration & dosage, Retinol-Binding Proteins immunology, Species Specificity, Th1 Cells metabolism, Uveitis immunology, Uveitis prevention & control, Autoimmune Diseases therapy, Interferon-gamma biosynthesis, Interleukin-17 physiology, Lymphocyte Activation immunology, Natural Killer T-Cells immunology, Natural Killer T-Cells metabolism, Th1 Cells immunology, Uveitis therapy
- Abstract
Invariant NKT cells (iNKT cells) have been reported to play a role not only in innate immunity but also to regulate several models of autoimmunity. Furthermore, iNKT cells are necessary for the generation of the prototypic eye-related immune regulatory phenomenon, anterior chamber associated immune deviation (ACAID). In this study, we explore the role of iNKT cells in regulation of autoimmunity to retina, using a model of experimental autoimmune uveitis (EAU) in mice immunized with a uveitogenic regimen of the retinal Ag, interphotoreceptor retinoid-binding protein. Natural strain-specific variation in iNKT number or induced genetic deficiencies in iNKT did not alter baseline susceptibility to EAU. However, iNKT function seemed to correlate with susceptibility and its pharmacological enhancement in vivo by treatment with iNKT TCR ligands at the time of uveitogenic immunization reproducibly ameliorated disease scores. Use of different iNKT TCR ligands revealed dependence on the elicited cytokine profile. Surprisingly, superior protection against EAU was achieved with alpha-C-GalCer, which induces a strong IFN-gamma but only a weak IL-4 production by iNKT cells, in contrast to the ligands alpha-GalCer (both IFN-gamma and IL-4) and OCH (primarily IL-4). The protective effect of alpha-C-GalCer was associated with a reduction of adaptive Ag-specific IFN-gamma and IL-17 production and was negated by systemic neutralization of IFN-gamma. These data suggest that pharmacological activation of iNKT cells protects from EAU at least in part by a mechanism involving innate production of IFN-gamma and a consequent dampening of the Th1 as well as the Th17 effector responses.
- Published
- 2008
- Full Text
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33. Abrogation of anti-retinal autoimmunity in IL-10 transgenic mice due to reduced T cell priming and inhibition of disease effector mechanisms.
- Author
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Agarwal RK, Horai R, Viley AM, Silver PB, Grajewski RS, Su SB, Yazdani AT, Zhu W, Kronenberg M, Murray PJ, Rutschman RL, Chan CC, and Caspi RR
- Subjects
- Animals, Antigen Presentation, Autoimmunity, Disease Models, Animal, Interleukin-10 genetics, Interleukin-10 metabolism, Lymphocyte Activation, Macrophages immunology, Macrophages metabolism, Major Histocompatibility Complex genetics, Mice, Mice, Inbred C57BL, Mice, Transgenic, T-Lymphocytes metabolism, Uveitis metabolism, Autoimmune Diseases immunology, Eye Proteins immunology, Interleukin-10 immunology, Retina immunology, Retinol-Binding Proteins immunology, T-Lymphocytes immunology, Uveitis immunology
- Abstract
Experimental autoimmune uveitis (EAU) induced by immunization of animals with retinal Ags is a model for human uveitis. The immunosuppressive cytokine IL-10 regulates EAU susceptibility and may be a factor in genetic resistance to EAU. To further elucidate the regulatory role of endogenous IL-10 in the mouse model of EAU, we examined transgenic (Tg) mice expressing IL-10 either in activated T cells (inducible) or in macrophages (constitutive). These IL-10-Tg mice and non-Tg wild-type controls were immunized with a uveitogenic regimen of the retinal Ag interphotoreceptor retinoid-binding protein. Constitutive expression of IL-10 in macrophages abrogated disease and reduced Ag-specific immunological responses. These mice had detectable levels of IL-10 in sera and in ocular extracts. In contrast, expression of IL-10 in activated T cells only partially protected from EAU and marginally reduced Ag-specific responses. All IL-10-Tg lines showed suppression of Ag-specific effector cytokines. APC from Tg mice constitutively expressing IL-10 in macrophages exhibited decreased ability to prime naive T cells, however, Ag presentation to already primed T cells was not compromised. Importantly, IL-10-Tg mice that received interphotoreceptor retinoid-binding protein-specific uveitogenic T cells from wild-type donors were protected from EAU. We suggest that constitutively produced endogenous IL-10 ameliorates the development of EAU by suppressing de novo priming of Ag-specific T cells and inhibiting the recruitment and/or function of inflammatory leukocytes, rather than by inhibiting local Ag presentation within the eye.
- Published
- 2008
- Full Text
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34. Villous B cells of the small intestine are specialized for invariant NK T cell dependence.
- Author
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Velázquez P, Wei B, McPherson M, Mendoza LM, Nguyen SL, Turovskaya O, Kronenberg M, Huang TT, Schrage M, Lobato LN, Fujiwara D, Brewer S, Arditi M, Cheng G, Sartor RB, Newberry RD, and Braun J
- Subjects
- Aging physiology, Animals, Antigen Presentation immunology, Antigens, CD1 genetics, Antigens, CD1 immunology, Antigens, CD1 metabolism, B-Lymphocytes cytology, Cell Movement immunology, Cell Separation, Intestinal Mucosa cytology, Intestinal Mucosa immunology, Intestine, Small cytology, Intestine, Small ultrastructure, Mice, Mice, Knockout, Microvilli immunology, Phenotype, Receptors, Antigen, B-Cell immunology, Sensitivity and Specificity, Signal Transduction immunology, B-Lymphocytes immunology, Intestine, Small immunology, T-Lymphocytes, Regulatory immunology
- Abstract
B cells are important in mucosal microbial homeostasis through their well-known role in secretory IgA production and their emerging role in mucosal immunoregulation. Several specialized intraintestinal B cell compartments have been characterized, but the nature of conventional B cells in the lamina propria is poorly understood. In this study, we identify a B cell population predominantly composed of surface IgM(+) IgD(+) cells residing in villi of the small intestine and superficial lamina propria of the large intestine, but distinct from the intraepithelial compartment or organized intestinal lymphoid structures. Small intestinal (villous) B cells are diminished in genotypes that alter the strength of BCR signaling (Bruton tyrosine kinase(xid), Galphai2(-/-)), and in mice lacking cognate BCR specificity. They are not dependent on enteric microbial sensing, because they are abundant in mice that are germfree or genetically deficient in TLR signaling. However, villous B cells are reduced in the absence of invariant NK T cells (Jalpha18(-/-) or CD1d(-/-) mice). These findings define a distinct population of conventional B cells in small intestinal villi, and suggest an immunologic link between CD1-restricted invariant NK T cells and this B cell population.
- Published
- 2008
- Full Text
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35. Cutting edge: activation by innate cytokines or microbial antigens can cause arrest of natural killer T cell patrolling of liver sinusoids.
- Author
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Velázquez P, Cameron TO, Kinjo Y, Nagarajan N, Kronenberg M, and Dustin ML
- Subjects
- Animals, Galactosylceramides administration & dosage, Galactosylceramides analysis, Hexuronic Acids administration & dosage, Hexuronic Acids analysis, Immunity, Innate, Killer Cells, Natural cytology, Killer Cells, Natural metabolism, Liver cytology, Liver metabolism, Mice, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets metabolism, Antigens, Bacterial physiology, Cell Migration Inhibition immunology, Cell Movement immunology, Cytokines physiology, Killer Cells, Natural immunology, Liver immunology, Lymphocyte Activation immunology, T-Lymphocyte Subsets immunology
- Abstract
Natural killer T (NKT) cells are innate-like lymphocytes that rapidly secrete large amounts of effector cytokines upon activation. Recognition of alpha-linked glycolipids presented by CD1d leads to the production of IL-4, IFN-gamma, or both, while direct activation by the synergistic action of IL-12 and IL-18 leads to IFN-gamma production only. We previously reported that in vitro cultured dendritic cells can modulate NKT cell activation and, using intravital fluorescence laser scanning microscopy, we reported that the potent stimulation of NKT cells results in arrest within hepatic sinusoids. In this study, we examine the relationship between murine NKT cell patrolling and activation. We report that NKT cell arrest results from activation driven by limiting doses of a bacteria-derived weak agonist, galacturonic acid-containing glycosphingolipid, or a synthetic agonist, alpha-galactosyl ceramide. Interestingly, NKT cell arrest also results from IL-12 and IL-18 synergistic activation. Thus, innate cytokines and natural microbial TCR agonists trigger sinusoidal NKT cell arrest and an effector response.
- Published
- 2008
- Full Text
- View/download PDF
36. Paradoxical effect of reduced costimulation in T cell-mediated colitis.
- Author
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Kim G, Levin M, Schoenberger SP, Sharpe A, and Kronenberg M
- Subjects
- Animals, Antigen-Presenting Cells immunology, Antigens, CD metabolism, Antigens, Differentiation metabolism, B7-1 Antigen genetics, B7-1 Antigen immunology, B7-2 Antigen genetics, B7-2 Antigen immunology, CD4-Positive T-Lymphocytes transplantation, CD40 Antigens immunology, CD40 Ligand immunology, CTLA-4 Antigen, Colitis pathology, Homeodomain Proteins genetics, Homeodomain Proteins immunology, Interleukin-2 antagonists & inhibitors, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, CD4-Positive T-Lymphocytes immunology, Colitis immunology, Interleukin-2 metabolism, Lymphocyte Activation
- Abstract
B7-1 and B7-2 play different roles in the pathogenesis of autoimmunity, but this is controversial. We analyzed colitis induced by transfer of CD45RB(high)CD4(+) T cells to RAG(-/-) recipients lacking B7-1 and/or B7-2. Surprisingly, disease was greatly accelerated in RAG(-/-) recipients deficient for either B7-1 or B7-2, especially in the B7-2(-/-) recipients. This accelerated colitis induction correlated with increased T cell division in vivo and production of Th1 cytokines. Although colitis pathogenesis following T cell transfer was inhibited in the absence of CD40L expression, CD40-CD40L interactions were not required in the B7-2(-/-) RAG(-/-) recipients. In vitro priming by APCs lacking either B7-1 or B7-2 caused decreased IL-2 production, which led to decreased CTLA-4 expression, although T cells primed in this way could respond vigorously upon restimulation by producing increased IL-2 and proinflammatory cytokines. Consistent with this mechanism, we demonstrate that blocking IL-2 early after T cell transfer accelerated colitis. Our data therefore outline a mechanism whereby synergistic costimulation by B7-1 and B7-2 molecules during priming is required for optimal IL-2 production. The consequent inhibitory effect of full CTLA-4 expression, induced by IL-2, may slow colitis, even in the absence of regulatory T cells.
- Published
- 2007
- Full Text
- View/download PDF
37. Mouse TCRalphabeta+CD8alphaalpha intraepithelial lymphocytes express genes that down-regulate their antigen reactivity and suppress immune responses.
- Author
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Denning TL, Granger SW, Mucida D, Graddy R, Leclercq G, Zhang W, Honey K, Rasmussen JP, Cheroutre H, Rudensky AY, and Kronenberg M
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, Gene Expression, Mice, Mice, Inbred C57BL, Oligonucleotide Array Sequence Analysis, Proteins genetics, CD8 Antigens analysis, CD8-Positive T-Lymphocytes immunology, Gene Expression Regulation, Immunity genetics, Receptors, Antigen, T-Cell, alpha-beta analysis, T-Lymphocyte Subsets immunology
- Abstract
Mouse small intestine intraepithelial lymphocytes (IEL) that express alphabetaTCR and CD8alphaalpha homodimers are an enigmatic T cell subset, as their specificity and in vivo function remain to be defined. To gain insight into the nature of these cells, we performed global gene expression profiling using microarray analysis combined with real-time quantitative PCR and flow cytometry. Using these methods, TCRalphabeta(+)CD8alphaalpha IEL were compared with their TCRalphabeta(+)CD8beta(+) and TCRgammadelta(+) counterparts. Interestingly, TCRalphabeta(+)CD8alphaalpha IEL were found to preferentially express genes that would be expected to down-modulate their reactivity. They have a unique expression pattern of members of the Ly49 family of NK receptors and tend to express inhibitory receptors, along with some activating receptors. The signaling machinery of both TCRalphabeta(+)CD8alphaalpha and TCRgammadelta(+) IEL is constructed differently than other IEL and peripheral T cells, as evidenced by their low-level expression of the linker for activation of T cells and high expression of the non-T cell activation linker, which suppresses T cell activation. The TCRalphabeta(+)CD8alphaalpha IEL subset also has increased expression of genes that could be involved in immune regulation, including TGF-beta(3) and lymphocyte activation gene-3. Collectively, these data underscore the fact that, while TCRalphabeta(+)CD8alphaalpha IEL resemble TCRgammadelta(+) IEL, they are a unique population of cells with regulated Ag reactivity that could have regulatory function.
- Published
- 2007
- Full Text
- View/download PDF
38. Invariant NKT cells amplify the innate immune response to lipopolysaccharide.
- Author
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Nagarajan NA and Kronenberg M
- Subjects
- Animals, Antigens, CD1 immunology, Antigens, CD1d, Lipopolysaccharides pharmacology, Lymphocyte Activation drug effects, Lymphocyte Activation immunology, Mice, Mice, Knockout, Cytokines immunology, Escherichia coli immunology, Immunity, Innate drug effects, Killer Cells, Natural immunology, Lipopolysaccharides immunology, T-Lymphocytes immunology
- Abstract
NKT cells are thought of as a bridge between innate and adaptive immunity. In this study, we demonstrate that mouse NKT cells are activated in response to Escherichia coli LPS, and produce IFN-gamma, but not IL-4, although activation through their TCR typically induces both IL-4 and IFN-gamma production. IFN-gamma production by NKT cells is dependent on LPS-induced IL-12 and IL-18 from APC. LPS induced IFN-gamma production by NKT cells does not require CD1d-mediated presentation of an endogenous Ag and exposure to a combination of IL-12 and IL-18 is sufficient to activate them. In mice that are deficient for NKT cells, innate immune cells are activated less efficiently in response to LPS, resulting in the reduced production of TNF and IFN-gamma. We propose that in addition to acting as a bridge to adaptive immunity, NKT cells act as an early amplification step in the innate immune response and that the rapid and complete initiation of this innate response depends on the early production of IFN-gamma by NKT cells.
- Published
- 2007
- Full Text
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39. Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice.
- Author
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Oertelt S, Lian ZX, Cheng CM, Chuang YH, Padgett KA, He XS, Ridgway WM, Ansari AA, Coppel RL, Li MO, Flavell RA, Kronenberg M, Mackay IR, and Gershwin ME
- Subjects
- Animals, Bile Ducts immunology, Bile Ducts pathology, CD4-Positive T-Lymphocytes pathology, CD8-Positive T-Lymphocytes pathology, Cell Movement genetics, Cell Movement immunology, Cytokines biosynthesis, Female, Liver immunology, Liver pathology, Liver Cirrhosis, Biliary pathology, Lymphocyte Subsets pathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Protein Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Species Specificity, Autoantibodies biosynthesis, Liver Cirrhosis, Biliary genetics, Liver Cirrhosis, Biliary immunology, Mitochondria immunology, Receptors, Transforming Growth Factor beta deficiency, Receptors, Transforming Growth Factor beta genetics
- Abstract
Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver, characterized by lymphocytic infiltrates in portal tracts, selective destruction of biliary epithelial cells, and anti-mitochondrial Abs (AMAs). The elucidation of early events in the induction of tissue inflammation and autoimmunity in PBC has been hampered by the cryptic onset of the disease, the practical limitations in accessing the target tissue, and the lack of a suitable animal model. We demonstrate in this study that a mouse transgenic for directed expression of a dominant-negative form of TGF-beta receptor type II (dnTGFbetaRII), under the direction of the CD4 promoter, mimics several key phenotypic features of human PBC, including spontaneous production of AMAs directed to the same mitochondrial autoantigens, namely PDC-E2, BCOADC-E2, and OGDC-E2. The murine AMAs also inhibit PDC-E2 activity. Moreover, there is lymphocytic liver infiltration with periportal inflammation analogous to the histological profile in human PBC. Additionally, the serum cytokine profile of affected mice mimics data in human PBC. The concomitant presence of these immunopathological features in the transgenic mice suggests that the TGF-betaRII pathway is implicated in the pathogenesis of PBC. Finally, these data point away from initiation of autoimmunity by mechanisms such as molecular mimicry and more toward activation of an intrinsically self-reactive T cell repertoire in which necessary regulatory T cell influences are lacking.
- Published
- 2006
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40. The complementarity determining region 2 of BV8S2 (V beta 8.2) contributes to antigen recognition by rat invariant NKT cell TCR.
- Author
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Pyz E, Naidenko O, Miyake S, Yamamura T, Berberich I, Cardell S, Kronenberg M, and Herrmann T
- Subjects
- Amino Acid Sequence, Animals, Antigens, CD1 genetics, Antigens, CD1 immunology, Antigens, CD1 metabolism, Antigens, CD1d, Cell Line, Cells, Cultured, Galactosylceramides administration & dosage, Galactosylceramides immunology, Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor, Gene Rearrangement, beta-Chain T-Cell Antigen Receptor, Immunophenotyping, Liver cytology, Liver immunology, Lymphocyte Subsets immunology, Lymphocyte Subsets metabolism, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Protein Binding genetics, Protein Binding immunology, Rats, Rats, Inbred F344, Receptors, Antigen, T-Cell, alpha-beta biosynthesis, Receptors, Antigen, T-Cell, alpha-beta genetics, Species Specificity, Antigen Presentation genetics, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Receptors, Antigen, T-Cell, alpha-beta metabolism, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism
- Abstract
Invariant NKT cells (iNKT cells) are characterized by a semi-invariant TCR comprising an invariant alpha-chain paired with beta-chains with limited BV gene usage which are specific for complexes of CD1d and glycolipid Ags like alpha-galactosylceramide (alpha-GalCer). iNKT cells can be visualized with alpha-GalCer-loaded CD1d tetramers, and the binding of mouse CD1d tetramers to mouse as well as to human iNKT cells suggests a high degree of conservation in recognition of glycolipid Ags between species. Surprisingly, mouse CD1d tetramers failed to stain a discrete cell population among F344/Crl rat liver lymphocytes, although comprised iNKT cells are indicated by IL-4 and IFN-gamma secretion after alpha-GalCer stimulation. The arising hypothesis that rat iNKT TCR recognizes alpha-GalCer only if presented by syngeneic CD1d was then tested with the help of newly generated rat and mouse iNKT TCR-transduced cell lines. Cells expressing mouse iNKT TCR reacted to alpha-GalCer presented by rat or mouse CD1d and efficiently bound alpha-GalCer-loaded mouse CD1d tetramers. In contrast, cells expressing rat iNKT TCR responded only to alpha-GalCer presented by syngeneic CD1d and bound mouse CD1d tetramers only poorly or not at all. Finally, CD1d-dependent alpha-GalCer reactivity and binding of mouse CD1d tetramers was tested for cells expressing iNKT TCR comprising either rat or mouse AV14 (Valpha14) alpha-chains and wild-type or mutated BV8S2 (Vbeta8.2) beta-chains. The results confirmed the need of syngeneic CD1d as restriction element for rat iNKT TCR and identified the CDR2 of BV8S2 as an essential site for ligand recognition by iNKT TCR.
- Published
- 2006
- Full Text
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41. Carboxylated glycans mediate colitis through activation of NF-kappa B.
- Author
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Srikrishna G, Turovskaya O, Shaikh R, Newlin R, Foell D, Murch S, Kronenberg M, and Freeze HH
- Subjects
- Animals, Antibodies, Antigen-Presenting Cells physiology, Apoptosis physiology, Cell Adhesion Molecules biosynthesis, Cell Adhesion Molecules genetics, Colitis immunology, Colitis prevention & control, Colon cytology, Colon immunology, Colon physiology, Cytokines antagonists & inhibitors, Disease Models, Animal, Endothelium cytology, Endothelium immunology, Endothelium physiology, Humans, Intestinal Mucosa cytology, Intestinal Mucosa immunology, Intestinal Mucosa physiology, Leukocytes immunology, Macrophages metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mucoproteins, NF-kappa B physiology, Polysaccharides immunology, Colitis metabolism, NF-kappa B metabolism, Polysaccharides physiology
- Abstract
The role of carbohydrate modifications of glycoproteins in leukocyte trafficking is well established, but less is known concerning how glycans influence pathogenesis of inflammation. We previously identified a carboxylate modification of N-linked glycans that is recognized by S100A8, S100A9, and S100A12. The glycans are expressed on macrophages and dendritic cells of normal colonic lamina propria, and in inflammatory infiltrates in colon tissues from Crohn's disease patients. We assessed the contribution of these glycans to the development of colitis induced by CD4(+)CD45RB(high) T cell transfer to Rag1(-/-) mice. Administration of an anti-carboxylate glycan Ab markedly reduced clinical and histological disease in preventive and early therapeutic protocols. Ab treatment reduced accumulation of CD4(+) T cells in colon. This was accompanied by reduction in inflammatory cells, reduced expression of proinflammatory cytokines and of S100A8, S100A9, and receptor for advanced glycation end products. In vitro, the Ab inhibited expression of LPS-elicited cytokines and induced apoptosis of activated macrophages. It specifically blocked activation of NF-kappaB p65 in lamina propria cells of colitic mice and in activated macrophages. These results indicate that carboxylate-glycan-dependent pathways contribute to the early onset of colitis.
- Published
- 2005
- Full Text
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42. Crystal structure of mouse CD1d bound to the self ligand phosphatidylcholine: a molecular basis for NKT cell activation.
- Author
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Giabbai B, Sidobre S, Crispin MD, Sanchez-Ruìz Y, Bachi A, Kronenberg M, Wilson IA, and Degano M
- Subjects
- Animals, Antigens, CD1 metabolism, Antigens, CD1d, Cell Line, Complementarity Determining Regions metabolism, Crystallography, X-Ray, Drosophila melanogaster, Killer Cells, Natural metabolism, Ligands, Mice, Models, Molecular, Phosphatidylcholines metabolism, Protein Binding immunology, Protein Isoforms chemistry, Protein Isoforms immunology, Protein Isoforms metabolism, Receptors, Antigen, T-Cell, alpha-beta metabolism, Recombinant Proteins chemistry, Recombinant Proteins immunology, Recombinant Proteins metabolism, Surface Properties, T-Lymphocyte Subsets metabolism, Antigens, CD1 chemistry, Antigens, CD1 immunology, Killer Cells, Natural immunology, Lymphocyte Activation immunology, Phosphatidylcholines chemistry, Phosphatidylcholines immunology, T-Lymphocyte Subsets immunology
- Abstract
NKT cells are immunoregulatory lymphocytes whose activation is triggered by the recognition of lipid Ags in the context of the CD1d molecules by the TCR. In this study we present the crystal structure to 2.8 A of mouse CD1d bound to phosphatidylcholine. The interactions between the ligand acyl chains and the CD1d molecule define the structural and chemical requirements for the binding of lipid Ags to CD1d. The orientation of the polar headgroup toward the C terminus of the alpha1 helix provides a rationale for the structural basis for the observed Valpha chain bias in invariant NKT cells. The contribution of the ligand to the protein surface suggests a likely mode of recognition of lipid Ags by the NKT cell TCR.
- Published
- 2005
- Full Text
- View/download PDF
43. Lack of chemokine receptor CCR5 promotes murine fulminant liver failure by preventing the apoptosis of activated CD1d-restricted NKT cells.
- Author
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Ajuebor MN, Aspinall AI, Zhou F, Le T, Yang Y, Urbanski SJ, Sidobre S, Kronenberg M, Hogaboam CM, and Swain MG
- Subjects
- Animals, Antigens, CD1d, Apoptosis genetics, Concanavalin A administration & dosage, Immunity, Innate genetics, Interleukin-4 biosynthesis, Interleukin-4 pharmacology, Killer Cells, Natural metabolism, Killer Cells, Natural pathology, Liver immunology, Liver metabolism, Liver pathology, Liver Failure, Acute genetics, Liver Failure, Acute prevention & control, Lymphocyte Activation genetics, Lymphocyte Depletion methods, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, CCR5 physiology, Spleen immunology, Spleen metabolism, Spleen pathology, T-Lymphocyte Subsets metabolism, T-Lymphocyte Subsets pathology, fas Receptor biosynthesis, fas Receptor physiology, Antigens, CD1 physiology, Apoptosis immunology, Killer Cells, Natural immunology, Liver Failure, Acute immunology, Liver Failure, Acute pathology, Receptors, CCR5 deficiency, Receptors, CCR5 genetics, T-Lymphocyte Subsets immunology
- Abstract
Fulminant liver failure (FLF) consists of a cascade of events beginning with a presumed uncontrolled systemic activation of the immune system. The etiology of FLF remains undefined. In this study, we demonstrate that CCR5 deficiency promotes the development of acute FLF in mice following Con A administration by preventing activated hepatic CD1d-restricted NKT cells (but not conventional T cells) from dying from activation-induced apoptosis. The resistance of CCR5-deficient NKT cells from activation-induced apoptosis following Con A administration is not due to a defective Fas-driven death pathway. Moreover, FLF in CCR5-deficient mice also correlated with hepatic CCR5-deficient NKT cells, producing more IL-4, but not IFN-gamma, relative to wild-type NKT cells. Furthermore, FLF in these mice was abolished by IL-4 mAb or NK1.1 mAb treatment. We propose that CCR5 deficiency may predispose individuals to the development of FLF by preventing hepatic NKT cell apoptosis and by regulating NKT cell function, establishing a novel role for CCR5 in the development of this catastrophic liver disease that is independent of leukocyte recruitment.
- Published
- 2005
- Full Text
- View/download PDF
44. Cutting edge: CD4+CD25+ regulatory T cells impaired for intestinal homing can prevent colitis.
- Author
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Denning TL, Kim G, and Kronenberg M
- Subjects
- Animals, Cell Movement genetics, Cells, Cultured, Coculture Techniques, Colitis immunology, Colitis pathology, Integrin beta Chains genetics, Integrin beta Chains physiology, Interferon-gamma antagonists & inhibitors, Interferon-gamma biosynthesis, Intestinal Mucosa metabolism, Lymphocyte Activation genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, T-Lymphocytes, Regulatory transplantation, Adoptive Transfer methods, Cell Movement immunology, Colitis prevention & control, Intestinal Mucosa cytology, Intestinal Mucosa immunology, Receptors, Interleukin-2 biosynthesis, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism
- Abstract
Transfer of CD4(+)CD45RB(high) T cells into RAG(-/-) mice causes colitis, which can be prevented by CD4(+)CD25(+) regulatory T cells (Treg). Colitis induction by CD4(+)CD45RB(high) T cells requires beta(7) integrin-dependent intestinal localization, but the importance of beta(7) integrins for Treg function is unknown. In this study, we show that beta(7)(-/-) Treg were effective in preventing colitis. Treg expanded in vivo to the same extent as CD4(+)CD45RB(high) T cells after transfer and they did not inhibit CD4(+)CD45RB(high) T cell expansion in lymphoid tissues, although they prevented the accumulation of Th1 effector cells in the intestine. beta(7)(-/-) Treg were significantly reduced in the large intestine, however, compared with wild-type Treg, and regulatory activity could not be recovered from the intestine of recipients of beta(7)(-/-) Treg. These data demonstrate that Treg can prevent colitis by inhibiting the accumulation of tissue-seeking effector cells and that Treg accumulation in the intestine is dispensable for colitis suppression.
- Published
- 2005
- Full Text
- View/download PDF
45. Cutting edge: IFN-gamma signaling to macrophages is required for optimal Valpha14i NK T/NK cell cross-talk.
- Author
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Wesley JD, Robbins SH, Sidobre S, Kronenberg M, Terrizzi S, and Brossay L
- Subjects
- Animals, Antigen Presentation, Cell Communication immunology, Dendritic Cells immunology, Dendritic Cells physiology, Galactosylceramides immunology, Immunophenotyping, Interferon-gamma immunology, Killer Cells, Natural immunology, Liver cytology, Macrophages immunology, Mice, Mice, Inbred C57BL, T-Lymphocytes immunology, T-Lymphocytes physiology, Interferon-gamma physiology, Killer Cells, Natural physiology, Lymphocyte Activation immunology, Macrophages physiology, Signal Transduction immunology
- Abstract
Activated NK T cells are known to rapidly stimulate NK cells and, subsequently, CD8(+) T cells and B cells. In this report, we first demonstrate that the downstream effects induced by alpha-galactosylceramide activated NK T cells on NK cells are mainly dependent on IFN-gamma. We found that NK T cell activation of NK cells requires a functional IFN-gamma signaling in macrophages and dendritic cells but not in B cells, NK cells, or NK T cells. NK T cell activation is dendritic cell-dependent whereas NK T cell activation of NK cells is indirect and in part mediated by macrophages. Interestingly, in this context, macrophage participation in the CD1d Ag presentation of alpha-galactosylceramide to NK T cells is not necessary. These data indicate that NK T cell-dependent activation of macrophages is required for optimal NK T cell-induced stimulation of NK cells.
- Published
- 2005
- Full Text
- View/download PDF
46. Molecular basis for the high affinity interaction between the thymic leukemia antigen and the CD8alphaalpha molecule.
- Author
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Attinger A, Devine L, Wang-Zhu Y, Martin D, Wang JH, Reinherz EL, Kronenberg M, Cheroutre H, and Kavathas P
- Subjects
- Amino Acid Sequence, Amino Acid Substitution, Animals, Base Sequence, Binding Sites genetics, CD8 Antigens chemistry, CD8 Antigens genetics, Conserved Sequence, DNA genetics, Humans, Hybridomas, In Vitro Techniques, Membrane Glycoproteins chemistry, Membrane Glycoproteins genetics, Mice, Mice, Inbred C57BL, Models, Molecular, Molecular Sequence Data, Protein Structure, Tertiary, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Sequence Homology, Amino Acid, T-Lymphocytes immunology, Transfection, CD8 Antigens metabolism, Membrane Glycoproteins metabolism
- Abstract
The mouse thymic leukemia (TL) Ag is a nonclassical MHC class I molecule that binds with higher affinity to CD8alphaalpha than CD8alphabeta. The interaction of CD8alphaalpha with TL is important for lymphocyte regulation in the intestine. Therefore, we studied the molecular basis for TL Ag binding to CD8alphaalpha. The stronger affinity of the TL Ag for CD8alphaalpha is largely mediated by three amino acids on exposed loops of the conserved alpha3 domain. Mutant classical class I molecules substituted with TL Ag amino acids at these positions mimic the ability to interact with CD8alphaalpha and modulate lymphocyte function. These data indicate that small changes in the alpha3 domain of class I molecules potentially can have profound physiologic consequences.
- Published
- 2005
- Full Text
- View/download PDF
47. The mouse CD1d cytoplasmic tail mediates CD1d trafficking and antigen presentation by adaptor protein 3-dependent and -independent mechanisms.
- Author
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Lawton AP, Prigozy TI, Brossay L, Pei B, Khurana A, Martin D, Zhu T, Späte K, Ozga M, Höning S, Bakke O, and Kronenberg M
- Subjects
- Adaptor Protein Complex 2 metabolism, Adaptor Protein Complex mu Subunits metabolism, Amino Acid Motifs, Amino Acid Sequence, Animals, Antigens, CD1 genetics, Antigens, CD1d, Cell Line, Glycosphingolipids immunology, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Kinetics, Mice, Mutagenesis, Site-Directed, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Adaptor Protein Complex 3 metabolism, Antigen Presentation, Antigens, CD1 chemistry, Antigens, CD1 metabolism
- Abstract
The short cytoplasmic tail of mouse CD1d (mCD1d) is required for its endosomal localization, for the presentation of some glycolipid Ags, and for the development of Valpha14i NKT cells. This tail has a four-amino acid Tyr-containing motif, Tyr-Gln-Asp-Ile (YQDI), similar to those sequences known to be important for the interaction with adaptor protein complexes (AP) that mediate the endosomal localization of many different proteins. In fact, mCD1d has been shown previously to interact with the AP-3 adaptor complex. In the present study, we mutated each amino acid in the YQDI motif to determine the importance of the entire motif sequence in influencing mCD1d trafficking, its interaction with adaptors, and its intracellular localization. The results indicate that the Y, D, and I amino acids are significant functionally because mutations at each of these positions altered the intracellular distribution of mCD1d and reduced its ability to present glycosphingolipids to NKT cells. However, the three amino acids are not all acting in the same way because they differ with regard to how they influence the intracellular distribution of CD1d, its rate of internalization, and its ability to interact with the mu subunit of AP-3. Our results emphasize that multiple steps, including interactions with the adaptors AP-2 and AP-3, are required for normal trafficking of mCD1d and that these different steps are mediated by only a few cytoplasmic amino acids.
- Published
- 2005
- Full Text
- View/download PDF
48. CD1d1 displayed on cell size beads identifies and enriches an NK cell population negatively regulated by CD1d1.
- Author
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Huang MM, Borszcz P, Sidobre S, Kronenberg M, and Kane KP
- Subjects
- Animals, Antibodies, Blocking pharmacology, Antigens, CD1 biosynthesis, Antigens, CD1 immunology, Antigens, CD1d, Cell Communication immunology, Cell Line, Tumor, Cell Size, Cells, Cultured, Female, Galactosylceramides metabolism, Immunosuppressive Agents immunology, Immunosuppressive Agents metabolism, Immunosuppressive Agents pharmacology, Interleukin-2 pharmacology, Killer Cells, Natural cytology, Lymphocyte Activation immunology, Lymphocyte Subsets cytology, Lymphocyte Subsets metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Protein Binding immunology, Receptors, Immunologic antagonists & inhibitors, Receptors, Immunologic biosynthesis, Receptors, Immunologic physiology, Receptors, KIR, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Antigens, CD1 metabolism, Antigens, CD1 physiology, Cytotoxicity, Immunologic immunology, Down-Regulation immunology, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Lymphocyte Subsets immunology, Microspheres
- Abstract
NK cells destroy microbe-infected cells while sparing healthy cells, and are controlled, in part, by inhibitory receptors specific for class I Ag-presenting molecules. CD1d1, a beta(2)-microglobulin-associated class I-like molecule, binds glycolipids and stimulates NKT cells. We previously demonstrated that target cell lysis by IL-2-activated mouse NK cells is inhibited by target cell expression of CD1d1, suggesting that IL-2-activated NK cells may express a CD1d1-specific inhibitory receptor. We now report that a significant subset of mouse IL-2-activated NK cells specifically binds cell size beads displaying either naturally expressed or recombinant CD1d1. In contrast, although tetramers of soluble recombinant CD1d1 loaded with alpha-galactosylceramide identify NKT cells, binding of this reagent to resting or IL-2-activated NK cells was undetectable, even with activated NK cells sorted with CD1d1 beads. Cytotoxicity by the CD1d1 bead-separated NK subset was strongly inhibited by CD1d1, compared with the NK cell subset not bound to CD1d1 beads. An Ab that blocks NKT cell recognition of CD1d1 also reverses CD1d1 inhibition of NK lysis, suggesting that TCRs of NKT cells and NK inhibitory receptor(s) may interact with a similar site on CD1d1. These results provide direct evidence for a physical interaction of NK cells with CD1d1, mediated by a functional, CD1d1-specific low-affinity inhibitory NK receptor. Display of ligands on cell size beads to maximize multivalent interaction may offer an alternative approach to examine NK cell receptor-ligand interactions, particularly those of lower expression and/or lower affinity/avidity that may go undetected using tetrameric reagents.
- Published
- 2004
- Full Text
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49. Glycolipid antigen drives rapid expansion and sustained cytokine production by NK T cells.
- Author
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Crowe NY, Uldrich AP, Kyparissoudis K, Hammond KJ, Hayakawa Y, Sidobre S, Keating R, Kronenberg M, Smyth MJ, and Godfrey DI
- Subjects
- Animals, Antigens pharmacology, Cell Division immunology, Cell Separation, Cell Survival immunology, Down-Regulation immunology, Galactosylceramides pharmacology, Injections, Intraperitoneal, Interferon-gamma biosynthesis, Interleukin-4 biosynthesis, Killer Cells, Natural metabolism, Liver cytology, Liver immunology, Lymphocyte Activation immunology, Mice, Mice, Inbred C57BL, Organ Specificity immunology, Receptors, Immunologic antagonists & inhibitors, Receptors, Immunologic biosynthesis, T-Lymphocyte Subsets metabolism, Time Factors, Antigens administration & dosage, Galactosylceramides administration & dosage, Galactosylceramides immunology, Killer Cells, Natural cytology, Killer Cells, Natural immunology, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets immunology
- Abstract
NKT cells are enigmatic lymphocytes that respond to glycolipid Ags presented by CD1d. Although they are key immunoregulatory cells, with a critical role in immunity to cancer, infection, and autoimmune diseases, little is known about how they respond to antigenic challenge. Current theories suggest that NKT cells die within hours of stimulation, implying that their direct impact on the immune system derives from the initial cytokine burst released before their death. Here we show that NKT cell disappearance results from TCR down-regulation rather than apoptosis, and that they expand to many times their normal number in peripheral tissues within 2-3 days of stimulation, before contracting to normal numbers over subsequent days. This expansion is associated with ongoing cytokine production, biased toward a Th1 (IFN-gamma(+) IL-4(-)) phenotype, in contrast to their initial Th0 (IFN-gamma(+)IL-4(+)) phenotype. This study provides critical new insight into how NKT cells can have such a major impact on immune responses, lasting many days beyond the initial stimulation of these cells.
- Published
- 2003
- Full Text
- View/download PDF
50. An anti-inflammatory role for V alpha 14 NK T cells in Mycobacterium bovis bacillus Calmette-Guérin-infected mice.
- Author
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Dieli F, Taniguchi M, Kronenberg M, Sidobre S, Ivanyi J, Fattorini L, Iona E, Orefici G, De Leo G, Russo D, Caccamo N, Sireci G, Di Sano C, and Salerno A
- Subjects
- Animals, Cells, Cultured, Colony Count, Microbial, Granuloma genetics, Granuloma microbiology, Granuloma pathology, Granuloma prevention & control, Immunophenotyping, Interferon-gamma biosynthesis, Killer Cells, Natural metabolism, Liver immunology, Liver microbiology, Lung immunology, Lung microbiology, Lymphocyte Depletion, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Mycobacterium bovis growth & development, T-Lymphocyte Subsets metabolism, Tuberculosis genetics, Tuberculosis immunology, Tumor Necrosis Factor-alpha biosynthesis, Up-Regulation genetics, Up-Regulation immunology, Killer Cells, Natural immunology, Liver pathology, Lung pathology, Mycobacterium bovis immunology, Receptors, Antigen, T-Cell, alpha-beta physiology, T-Lymphocyte Subsets immunology, Tuberculosis pathology, Tuberculosis prevention & control
- Abstract
The possible contribution of NKT cells to resistance to Mycobacterium tuberculosis infection remains unclear. In this paper we characterized the Valpha14 NKT cell population following infection with Mycobacterium bovis bacillus Calmette-Guérin (BCG). BCG infection determined an early expansion of Valpha14 NKT cells in liver, lungs, and spleen, which peaked on day 8 and was sustained until day 30. However, an NK1.1(+) Valpha14 NKT population preferentially producing IFN-gamma predominated at an early stage (day 8), which was substituted by an NK1.1(-) population preferentially producing IL-4 at later stages (day 30). Despite the fact that Valpha14 NKT cell-deficient mice eliminated BCG as did control mice, they had significantly higher numbers of granulomas in liver and lungs. Additionally, while control mice developed organized small granulomas, those in Valpha14 NKT-deficient mice had signs of caseation, large cellular infiltrates, and some multinucleated macrophages, suggesting that Valpha14 NKT cells may actually work as anti-inflammatory cells by limiting excessive lymphocyte influx and tissue pathology. In agreement, we found an increased spontaneous production and mRNA expression of TNF-alpha in liver and lungs of Valpha14 NKT-deficient mice, whose neutralization in vivo by anti-TNF-alpha mAbs consistently reduced the number of granulomas in liver and lungs. Together, our results support a regulatory role for Valpha14 NKT cells in the course of BCG infection through their ability to limit the extent of inflammatory response and point to an important role for this cell subset as a regulator of the balance between protective responses and immunopathology.
- Published
- 2003
- Full Text
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