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CD4+ helper T (Th) cells differentiate toward distinct effector cell lineages characterized by their distinct cytokine expression patterns and functions. Multiple Th cell populations secrete IL-22 that contributes to both protective and pathological inflammatory responses. Although the differentiation of lL-22-producing Th cells is controlled by the aryl hydrocarbon receptor (AhR), little is known about the regulatory mechanisms inducing physiological stimulators for AhR. Here, we show that Notch signaling enhances IL-22 production by CD4+T cells by a mechanism involving AhR stimulation. Notch-mediated stimulation of CD4+ T cells increased the production of IL-22 even in the absence of STAT3. CD4+ T cells from RBP-J-deficient mice had little ability to produce lL-22 through T cell receptor-mediated stimulation. RBP-J-deficient mice were highly susceptible to the detrimental immunopathology associ- ated with ConA-induced hepatitis with little IL-22 production by CD4+ T cells. Exogenous lL-22 protected RBP-J-deficient mice from ConA-induced hepatitis. Notch signaling promoted production of endogenous stimulators for AhR, which further augmented IL-22 secretion. Our studies identify a Notch-AhR axis that regulates IL- 22 expression and fine-tunes immune system control of inflammatory responses. [ABSTRACT FROM AUTHOR]

Murine γδ T cells participate in the innate immune response against infection by an intracellular pathogen Listeria monocytogenes. Vδ1+γδ T cells coexpressing Vγ6 are a major γδ T-cell subpopulation induced at an early stage of L. monocytogenes infection in the livers of infected mice. To investigate the protective role of the Vγ6/Vδ1+γδ T cells against L. monocytogenes infection, Vδ1 gene-deficient (Vδ1−/−) mice were analysed because these mice selectively lacked a Vγ6/Vδ1+γδ T-cell subpopulation in the L. monocytogenes-infected liver. The Vδ1−/− mice showed increased bacterial burden in the liver and spleen, and decreased survival rate at an early stage of L. monocytogenes infection when compared to wild-type mice. Histological examination showed abscess-like lesions and unorganized distribution of macrophages in the liver of the Vδ1−/− mice but not in the wild-type mice after L. monocytogenes infection. The Vγ6/Vδ1+γδ T cells produced interferon-γ and interleukin-17A. All the results suggest that murine Vγ6/Vδ1+γδ T cells control the innate protective response against L. monocytogenes infection through production of the proinflammatory cytokines interferon-γ and interleukin-17A in the infected liver. [ABSTRACT FROM AUTHOR]

Background: Although an immunomodulatory role for estrogens has long been demonstrated by experimental and clinical observations, the mechanism by which estrogens exert their effect on T cells has not been clearly defined. Methods: In this study we analyzed the effects of β-estradiol (E2), at its contraceptive dose, on the delayed-type hypersensitivity (DTH) to purified protein derivatives (PPD) and associated immune response in female mice. Results: E2 treatment decreased PPD-specific DTH response, which coincided with a decrease in the leukocytes numbers in the draining lymph nodes (DLN) and spleen compared with control mice. E2 treatment also suppressed the in vitro PPD-specific proliferative response of DLN and spleen cells from PPD-primed mice. The analysis of production and gene expression of cytokines by DLN cells demonstrated that E2 treatment suppressed IL-2 and IFN-γ production in response to PPD in vitro. In contrast, IL-4 and IL-10 gene expression by DLN cells of E2-treated mice, taken 24 h after in vivo restimulation of mice with PPD, was enhanced. Furthermore, we found that spleen APC from E2-treated mice failed to induce optimum proliferation of the PPD-primed T cells in response to PPD in vitro. The impaired APC function by E2 was not due to induction of suppressor cell activity because addition of the normal spleen APC to APC from E2-treated mice restored the proliferative response of the PPD-primed T cells in response to PPD. Conclusion: Our results suggest that the E2-mediated inhibition of DTH reaction is due to a combination of the down regulation of APC function and deviation of the immune response from Th1-type to Th2-type.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Presents a study evaluating the requirement for the Src-related tyrosine kinase p56lck in the development of T cells that have gammadelta TCRs, which generally do not express CD4 or CD8, by breeding p56lck mutant mice with TCRgammadelta transgenic mice. CD4-CD8- precursors transient expression of the interleukin-2 receptor alpha chain; Need for p56lck for thymic development of gammadelta+ T cells; More.

Immature CD4+CD8+ double-positive (DP) thymocytes are positively selected for further development if they express TCR reacting with thymic ligands of low affinity. However, the majority of DP thymocytes express low TCR levels. This low level of TCR may be insufficient to recognize thymic ligands. To understand the basis for the low expression of TCR on DP thymocytes, we determined the density of TCR expression at various stages of their development using TCR transgenic (TCR-Tg) mice. We found that TCR expression was high in the thymocytes that had recently transited into the DP stage but then gradually decreased on DP cells if they were not selected by TCR interaction with MHC molecules. However, such TCR suppression was not observed in positively selected DP cells and in the non-selected DP cells obtained from CD45 deficient mice or from mice receiving anti-CD4 mAb. These findings suggest that the once highly expressed TCR at the DP stage is suppressed by CD45 and/or CD4 on non-selected thymocytes. Furthermore, TCR suppression is prevented by TCR-mediated signals. The maintenance of high TCR levels on positively selected DP thymocytes may facilitate their selection. [ABSTRACT FROM AUTHOR]

The gastrointestinal tract comes into direct contact with environmental agents, including bacteria, viruses, and foods. Intestine-specific subsets of immune cells maintain gut homeostasis by continuously sampling luminal antigens and maintaining immune tolerance. CD11c(+)CX3CR1(+) cells sample luminal antigens in the small intestine and contribute to the trafficking of bacteria to lymph nodes under dysbiotic conditions. The molecular mechanisms crucial for the differentiation of CD11c(+)CX3CR1(+) cells remain unclear. Here we demonstrate that the Notch1- or Notch2-Rbpj axis is essential for the development of CD11c(+)CX3CR1(+) cells. In mice in which Rbpj or Notch1 and Notch2 were deleted from CD11c(+) cells, there was a deficit of CD11c(+)CX3CR1(+) cells and an accumulation of CD11c(low)CX3CR1(+) cells. The CD11c(low)CX3CR1(+) cells could not differentiate to CD11c(+)CX3CR1(+) cells, suggesting that CD11c(low)CX3CR1(+) cells represent a lineage distinct from CD11c(+)CX3CR1(+) cells. These data indicate that Notch signaling is essential for lineage fixation of intestinal CD11c(+)CX3CR1(+) cells.

Neutrophils infiltrate the site of infection and play critical roles in host defense, especially against extracellular bacteria. In the present study, we found a rapid and transient production of IL-17 after i.p. infection with Escherichia coli, preceding the influx of neutrophils. Neutralization of IL-17 resulted in a reduced infiltration of neutrophils and an impaired bacterial clearance. Ex vivo intracellular cytokine flow cytometric analysis revealed that gammadelta T cell population was the major source of IL-17. Mice depleted of gammadelta T cells by mAb treatment or mice genetically lacking Vdelta1 showed diminished IL-17 production and reduced neutrophil infiltration after E. coli infection, indicating an importance of Vdelta1(+) gammadelta T cells as the source of IL-17. It was further revealed that gammadelta T cells in the peritoneal cavity of naive mice produced IL-17 in response to IL-23, which was induced rapidly after E. coli infection in a TLR4 signaling-dependent manner. Thus, although gammadelta T cells are generally regarded as a part of early induced immune responses, which bridge innate and adaptive immune responses, our study demonstrated a novel role of gammadelta T cells as a first line of host defense controlling neutrophil-mediated innate immune responses.

An influx of neutrophils followed a short time later by an influx of macrophages to the infected site plays a key role in innate immunity against Escherichia coli infection. We found in this study that Vdelta1-/- mice exhibited impaired accumulation of peritoneal macrophages but not neutrophils and delayed bacterial clearance after i.p. inoculation with E. coli. Peritoneal gammadelta T cells from E. coli-infected wild-type mice produced CCL3/MIP-1alpha and CCL5/RANTES in response to gammadelta TCR triggering in vitro, whereas such production was not evident in gammadelta T cells from E. coli-infected Vdelta1-/- mice. Neutralization of CCL3/MIP-1alpha by a specific mAb in vivo significantly inhibited the accumulation of macrophages in the peritoneal cavity after E. coli infection, resulting in exacerbated bacterial growth in the peritoneal cavity. These results suggest that Vdelta1+ gammadelta T cells bridge a gap between neutrophils and macrophages in innate immunity during E. coli infection mediated by production of CC chemokines, enhancing macrophage trafficking to the site of infection.

Background: The allogeneic islets transplantation is an ideal therapeutic strategy for patients with diabetes mellitus. However, it has been difficult to induce immunological tolerance against islets grafts. The CD4+CD25+ regulatory T-cells (Treg) play a role in suppressing T-cell activation. Thus, we evaluated whether Treg can regulate donor-specific T-cell tolerance that received allogeneic islets into the hepatic parenchyma (ITxHP) along with Treg., Methods: C3H/He mice were used as donors; and streptozotocin-induced diabetic BALB/c mice were recipients. The protocol included three groups: Group A recipients received only 300 IE islets; Group B was given 300 IE islets and whole splenocytes; Group C was given 300 IE islets and Treg purified from peripheral lymph nodes., Results: For all mice in Groups A and B, the fasting blood sugar exceeded 250mg/dl and graft rejection was observed. GVHD was observed earlier in Group B than in Group A. In contrast graft survival exceeded 30 days for two mice in Group C (50%, mean POD 28.5 +/- 24.0, P<0.05). Mixed lymphocyte reaction showed that T-cells from tolerant mice had very weak responses against spleen cells from C3H mice., Conclusions: The simultaneous ITxHP with CD4+CD25+ T-cells administration prolonged islet graft survivals and induced donor-specific hyporesponsiveness.

Murine gamma delta T cells participate in innate immune response against infection of the intracellular bacterium Listeria monocytogenes. In the present report, we analyzed the mechanism of the gamma delta T cell-mediated response against L. monocytogenes infection. gamma delta T cell-enriched spleen cells of L. monocytogenes-infected mice produced IFN-gamma in vitro in response to L. monocytogenes-infected spleen cells. The IFN-gamma production was abrogated by depletion of Vgamma1+ gamma delta T cells. IFN-gamma production of the Vgamma1+ gamma delta T cells in response to L. monocytogenes-infected spleen cells required IL-12. However, addition of Fab fragment of anti-TCR gamma delta monoclonal antibodies (mAb) failed to block the response, suggesting that the response requires no TCR-mediated antigen recognition. Interestingly, Vgamma1+ gamma delta T cells of naive mice also produced IFN-gamma in response to L. monocytogenes-infected spleen cells in an IL-12-dependent manner. Furthermore, the IL-12 receptor (IL-12R) gene was expressed on the Vgamma1+ gamma delta T cells of naive mice as well as those of L. monocytogenes-infected mice although naive alpha beta T cells lack IL-12R expression. All the results suggest that the Vgamma1+ gamma delta T cells participate in immune surveillance against intracellular bacterial infection through quick production of IFN-gamma in response to infection-induced IL-12 without antigen-driven clonal expansion and maturation.