31 results on '"Konieczny, Bogumila"'
Search Results
2. Rescue of exhausted CD8 T cells by PD-1–targeted therapies is CD28-dependent
- Author
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Kamphorst, Alice O., Wieland, Andreas, Nasti, Tahseen, Yang, Shu, Zhang, Ruan, Barber, Daniel L., Konieczny, Bogumila T., Daugherty, Candace Z., Koenig, Lydia, Yu, Ke, Sica, Gabriel L., Sharpe, Arlene H., Freeman, Gordon J., Blazar, Bruce R., Turka, Laurence A., Owonikoko, Taofeek K., Pillai, Rathi N., Ramalingam, Suresh S., Araki, Koichi, and Ahmed, Rafi
- Published
- 2017
3. Recall and Propagation of Allospecific Memory T Cells Independent of Secondary Lymphoid Organs
- Author
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Chalasani, Geetha, Dai, Zhenhua, Konieczny, Bogumila T., Baddoura, Fady K., and Lakkis, Fadi G.
- Published
- 2002
4. Effector CD8 T cells dedifferentiate into long-lived memory cells
- Author
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Youngblood, Ben, Hale, Scott J., Kissick, Haydn T., Ahn, Eunseon, Xu, Xiaojin, Wieland, Andreas, Araki, Koichi, West, Erin E., Ghoneim, Hazem E., Fan, Yiping, Dogra, Pranay, Davis, Carl W., Konieczny, Bogumila T., Antia, Rustom, Cheng, Xiaodong, and Ahmed, Rafi
- Published
- 2017
- Full Text
- View/download PDF
5. Regulation of homeostatic chemokine expression and cell trafficking during immune responses
- Author
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Mueller, Scott N., Hosiawa-Meagher, Karoline A., Konieczny, Bogumila T., Sullivan, Brandon M., Bachmann, Martin F., LocksLey, Richard M., Ahmed, Rafi, and Matloubian, Mehrdad
- Subjects
Chemokines -- Research ,Dendritic cells -- Research ,Immune response -- Research ,Lymphocytes -- Research - Published
- 2007
6. Tight Regulation of Memory CD8+ T Cells Limits Their Effectiveness during Sustained High Viral Load
- Author
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West, Erin E., Youngblood, Ben, Tan, Wendy G., Jin, Hyun-Tak, Araki, Koichi, Alexe, Gabriela, Konieczny, Bogumila T., Calpe, Silvia, Freeman, Gordon J., Terhorst, Cox, Haining, Nicholas W., and Ahmed, Rafi
- Published
- 2011
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- View/download PDF
7. CD8 T-cell memory differentiation program: what dictates effector and memory heterogeneity?: 024
- Author
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Kalia, Vandana, Sarkar, Surojit, Haining, Nicholas W., Konieczny, Bogumila, Subramaniam, Shruti, and Ahmed, Rafi
- Published
- 2009
8. Immunologic determinants of susceptibility to experimental glomerulonephritis: Role of cellular immunity
- Author
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Coelho, Sandra N., Saleem, Sohail, Konieczny, Bogumila T., Parekh, Kannan R., Baddoura, Fady K., and Lakkis, Fadi G.
- Published
- 1997
9. Immunologic 'ignorance' of vascularized organ transplants in the absence of secondary lymphoid tissue
- Author
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Lakkis, Fadi G., Arakelov, Alexandr, Konieczny, Bogumila T., and Inoue, Yoshihiko
- Abstract
Author(s): Fadi G. Lakkis (corresponding author) [1]; Alexandr Arakelov [1]; Bogumila T. Konieczny [1]; Yoshihiko Inoue [1] Secondary lymphoid organs (the spleen, lymph nodes and mucosal lymphoid tissues) provide the [...]
- Published
- 2000
- Full Text
- View/download PDF
10. PD-1+ stemlike CD8 T cells are resident in lymphoid tissues during persistent LCMV infection.
- Author
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Se Jin Im, Konieczny, Bogumila T., Hudson, William H., Masopust, David, and Ahmed, Rafi
- Subjects
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T cells , *LYMPHOID tissue , *LYMPHOCYTIC choriomeningitis virus , *VIRUS diseases - Abstract
The migratory patterns of virus-specific CD8 T cells during chronic viral infection are not well understood. To address this issue, we have done parabiosis experiments during chronic lymphocytic choriomeningitis virus (LCMV) infection of mice. We found that despite the high frequency of virus-specific CD8 T cells in both lymphoid and nonlymphoid tissues there was minimal migration of virus-specific CD8 T cells between the chronically infected conjoined parabiont mice. This was in contrast to parabionts between mice that had undergone an acute LCMV infection where virus-specific CD8 T cells established equilibrium demonstrating circulation of memory T cells generated after viral clearance. We have identified a population of PD-1+ TCF1+CXCR5+Tim-3- stemlike virus-specific CD8 T cells that reside in lymphoid tissues and act as resource cells for maintaining the T cell response during chronic infection. These are the cells that proliferate and give rise to the more terminally differentiated PD-1+ CXCR5-Tim-3+ CD8 T cells. Both the stemlike CD8 T cells and their terminally differentiated progeny showed minimal migration during chronic infection and the few LCMV-specific CD8 T cells that were present in circulation were the recently emerging progeny from the stemlike CD8 T cells. The PD-1+ TCF1+CXCR5+ stemlike CD8 T cells were truly resident in lymphoid tissues and did not circulate in the blood. We propose that this residency in specialized niches within lymphoid tissues is a key aspect of their biology and is essential for maintaining their quiescence and stemlike program under conditions of a chronic viral infection. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
11. Autophagy is essential for effector CD8+ T cell survival and memory formation.
- Author
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Xu, Xiaojin, Araki, Koichi, Li, Shuzhao, Han, Jin-Hwan, Ye, Lilin, Tan, Wendy G, Konieczny, Bogumila T, Bruinsma, Monique W, Martinez, Jennifer, Pearce, Erika L, Green, Douglas R, Jones, Dean P, Virgin, Herbert W, and Ahmed, Rafi
- Subjects
AUTOPHAGY ,T cells ,IMMUNOLOGIC memory ,ANIMAL models for virus diseases ,LABORATORY mice ,LYMPHOCYTIC choriomeningitis virus ,CELL proliferation - Abstract
The importance of autophagy in the generation of memory CD8
+ T cells in vivo is not well defined. We report here that autophagy was dynamically regulated in virus-specific CD8+ T cells during acute infection of mice with lymphocytic choriomeningitis virus. In contrast to the current paradigm, autophagy decreased in activated proliferating effector CD8+ T cells and was then upregulated when the cells stopped dividing just before the contraction phase. Consistent with those findings, deletion of the gene encoding either of the autophagy-related molecules Atg5 or Atg7 had little to no effect on the proliferation and function of effector cells, but these autophagy-deficient effector cells had survival defects that resulted in compromised formation of memory T cells. Our studies define when autophagy is needed during effector and memory differentiation and warrant reexamination of the relationship between T cell activation and autophagy. [ABSTRACT FROM AUTHOR]- Published
- 2014
- Full Text
- View/download PDF
12. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells.
- Author
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Kaech, Susan M., Tan, Joyce T., Wherry, E. John, Konieczny, Bogumila T., Surh, Charles D., and Ahmed, Rafi
- Subjects
INTERLEUKINS ,T cells - Abstract
A major unanswered question is what distinguishes the majority of activated CD8 T cells that die after an acute viral infection from the small fraction (5-10%) that survive to become long-lived memory cells. In this study we show that increased expression of the interleukin 7 receptor a-chain (IL-7Ra) identifies the effector CD8 T cells that will differentiate into memory cells. IL-7R
hi effector cells contained increased amounts of antiapoptotic molecules, and adoptive transfer of IL-7Rhi and IL-7Rlo effector cells showed that IL-7Rhi cells preferentially gave rise to memory cells that could persist and confer protective immunity. Thus, selective expression of IL-7R identifies memory cell precursors, and this marker may be useful in predicting the number of memory T cells generated after infection or immunization. [ABSTRACT FROM AUTHOR]- Published
- 2003
- Full Text
- View/download PDF
13. Recall and propagation of allospecific memory T cells independent of secondary lymphoid organs.
- Author
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Chalasanni, Geetha, Zhenhua Sai, Konieczny, Bogumila T., Baddoura, Fady K., and Lakkis, Fadi G.
- Subjects
T cells ,LYMPHOID tissue ,EPITOPES - Abstract
Focuses on the implication of allospecific memory T cells on the lymphoid tissue. Absence of antigenic determinants; Observation of the peritoneal membrane; Formation of lymph node cells.
- Published
- 2002
14. ALLOANTIGEN-DRIVEN T CELL DEATH MEDIATED BY FAS LIGAND AND TUMOR NECROSIS FACTOR-α IS NOT ESSENTIAL FOR THE INDUCTION OF ALLOGRAFT ACCEPTANCE1.
- Author
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Wagener, Maylene E., Konieczny, Bogumila T., Dai, Zhenhua, Ring, Guido H., and Lakkis, Fadi G.
- Published
- 2000
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- View/download PDF
15. Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection
- Author
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Penaloza-MacMaster, Pablo, Kamphorst, Alice O., Wieland, Andreas, Araki, Koichi, Iyer, Smita S., West, Erin E., O’Mara, Leigh, Yang, Shu, Konieczny, Bogumila T., Sharpe, Arlene H., Freeman, Gordon J., Rudensky, Alexander Y., and Ahmed, Rafi
- Abstract
Regulatory T (T reg) cells are critical for preventing autoimmunity mediated by self-reactive T cells, but their role in modulating immune responses during chronic viral infection is not well defined. To address this question and to investigate a role for T reg cells in exhaustion of virus-specific CD8 T cells, we depleted T reg cells in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). T reg cell ablation resulted in 10–100-fold expansion of functional LCMV-specific CD8 T cells. Rescue of exhausted CD8 T cells was dependent on cognate antigen, B7 costimulation, and conventional CD4 T cells. Despite the striking recovery of LCMV-specific CD8 T cell responses, T reg cell depletion failed to diminish viral load. Interestingly, T reg cell ablation triggered up-regulation of the molecule programmed cell death ligand-1 (PD-L1), which upon binding PD-1 on T cells delivers inhibitory signals. Increased PD-L1 expression was observed especially on LCMV-infected cells, and combining T reg cell depletion with PD-L1 blockade resulted in a significant reduction in viral titers, which was more pronounced than that upon PD-L1 blockade alone. These results suggest that T reg cells effectively maintain CD8 T cell exhaustion, but blockade of the PD-1 inhibitory pathway is critical for elimination of infected cells.
- Published
- 2014
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- View/download PDF
16. INTERFERON-γ IS NECESSARY FOR INITIATING THE ACUTE REJECTION OF MAJOR HISTOCOMPATIBILITY COMPLEX CLASS II-DISPARATE SKIN ALLOGRAFTS1.
- Author
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Ring, Guido H., Saleem, Sohail, Dai, Zhenhua, Hassan, Ali Taha, Konieczny, Bogumila T., Baddoura, Fady K., and Lakkis, Fadi G.
- Published
- 1999
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17. ACUTE REJECTION OF VASCULARIZED HEART ALLOGRAFTS IN THE ABSENCE OF IFNγ,.
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Saleem, Sohail, Konieczny, Bogumila T., Lowry, Robin P., Baddoura, Fady K., and Lakkis, Fadi G.
- Published
- 1996
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18. THE KEY ROLE OF SECONDARY LYMPHOID ORGANS IN THE REJECTION OF VASCULARIZED ALLOGRAFTS.
- Author
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Arakelov, Alexandr, Konieczny, Bogumila T., Inoue, Yoshihiko, and Lakkis, Fadi G.
- Published
- 2000
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19. GENERATION AND MAINTENANCE OF ALLOSPECIFIC CD8+ MEMORY T CELLS IN THE ABSENCE OF INTERLEUKIN-2.
- Author
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Dai, Zhenhua, Konieczny, Bogumila T., and Lakkis, Fadi G.
- Published
- 2000
- Full Text
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20. Adenovirus Serotype 5 Vaccination Results in Suboptimal CD4 T Helper 1 Responses in Mice.
- Author
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Junghwa Lee, Masao Hashimoto, Se Jin Im, Koichi Araki, Hyun-Tak Jin, Davis, Carl W., Konieczny, Bogumila T., Spies, Gregory A., McElrath, M. Juliana, and Ahmed, Rafi
- Subjects
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ADENOVIRUS diseases , *SEROTYPES , *LABORATORY mice , *LYMPHOCYTIC choriomeningitis , *VIRUS diseases , *CD4 antigen - Abstract
Adenovirus serotype 5 (Ad5) is one of the most widely used viral vectors and is known to generate potent T cell responses. While many previous studies have characterized Ad5-induced CD8 T cell responses, there is a relative lack of detailed studies that have analyzed CD4 T cells elicited by Ad5 vaccination. Here, we immunized mice with Ad5 vectors encoding lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) and examined GP-specific CD4 T cell responses elicited by Ad5 vectors and compared them to those induced by an acute LCMV infection. In contrast to LCMV infection, where balanced CD4 T helper 1 (Th1) and T follicular helper (Tfh) responses were induced, Ad5 immunization resulted in a significantly reduced frequency of Th1 cells. CD4 T cells elicited by Ad5 vectors expressed decreased levels of Th1 markers, such as Tim3, SLAM, T-bet, and Ly6C, had smaller amounts of cytotoxic molecules like granzyme B, and produced less interferon gamma than CD4 T cells induced by LCMV infection. This defective CD4 Th1 response appeared to be intrinsic for Ad5 vectors and not a reflection of comparing a nonreplicating vector to a live viral infection, since immunization with a DNA vector expressing LCMV-GP generated efficient CD4 Th1 responses. Analysis at early time points (day 3 or 4) after immunization with Ad5 vectors revealed a defect in the expression of CD25 (interleukin-2 [IL-2] receptor alpha chain) on Ad5-elicited CD4 T cells, and administration of exogenous IL-2 following Ad5 immunization partially restored CD4 Th1 responses. These results suggest that impairment of Th1 commitment after Ad5 immunization could be due to reduced IL-2-mediated signaling. IMPORTANCE During viral infection, generating balanced responses of Th1 and Tfh cells is important to induce effective cell-mediated responses and provide optimal help for antibody responses. In this study, to investigate vaccine-induced CD4 T cell responses, we characterized CD4 T cells after immunization with Ad5 vectors expressing LCMV-GP in mice. Ad5 vectors led to altered effector differentiation of LCMV GP-specific CD4 T cells compared to that during LCMV infection. CD4 T cells following Ad5 immunization exhibited impaired Th1 lineage commitment, generating significantly decreased Th1 responses than those induced by LCMV infection. Our results suggest that suboptimal IL-2 signaling possibly plays a role in reduced Th1 development following Ad5 immunization. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
21. Interleukin-21 Is a Critical Cytokine for the Generation of Virus-Specific Long-Lived Plasma Cells.
- Author
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Ur Rasheed, Mohammed Ata, Latner, Donald R., Aubert, Rachael D., Gourley, Tania, Spolski, Rosanne, Davis, Carl W., Langley, William A., Ha, Sang-Jun, Sarkar, Surojit, Kalia, Vandana, Konieczny, Bogumila T., Leonard, Warren J., and Ahmed, Rafi
- Subjects
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INTERLEUKIN-21 , *CYTOKINES , *PLASMA cells , *BONE marrow , *IMMUNOGLOBULINS , *HUMORAL immunity , *VIRAL antigens - Abstract
Long-lived plasma cells that reside in the bone marrow constitutively produce antibody in the absence of antigen and are the cellular basis of durable humoral immunity. The generation of these long-lived plasma cells depends upon a series of highly or-chestrated interactions between antigen-specific CD4 T cells and B cells and the formation of germinal centers (GCs). In this study, we have examined the role of the cytokine interleukin-21 (IL-21 ) in regulating humoral immunity during acute viral infec-tions. Using IL-21 receptor-deficient (IL-21 R-/-) mice, we found that virus-specific CD4 T cells were generated after infection with lymphocytic choriomeningitis virus (LCMV) and that these CD4 T cells differentiated into T follicular helper (TFH)-like cells in the absence of IL-21 signaling. There was also no defect in the formation of GCs, although after day 15 these GCs disap-peared faster in IL-21R-/- mice than in wild-type mice. Isotype switching and the initial LCMV-specific IgG response were nor-mal in IL-21R-/- mice. However, these mice exhibited a profound defect in generating long-lived plasma cells and in sustaining antibody levels over time. Similar results were seen after infection of IL-21R-/- mice with vesicular stomatitis virus and influ-enza virus. Using chimeric mice containing wild-type or IL-21 R-/- CD4 T cells and B cells, we showed that both B and CD4 T cells need IL-21 signaling for generating long-term humoral immunity. Taken together, our results highlight the importance of IL-21 in humoral immunity to viruses. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
22. Tight Regulation of Memory CD8+ T Cells Limits Their Effectiveness during Sustained High Viral Load
- Author
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West, Erin E., Youngblood, Ben, Tan, Wendy G., Jin, Hyun-Tak, Araki, Koichi, Alexe, Gabriela, Konieczny, Bogumila T., Calpe, Silvia, Freeman, Gordon J., Terhorst, Cox, Haining, W. Nicholas, and Ahmed, Rafi
- Subjects
- *
GENETIC regulation , *VIRAL load , *CHRONIC diseases , *ENZYME inhibitors , *T cell receptors , *CELL proliferation , *VACCINATION - Abstract
Summary: To design successful vaccines for chronic diseases, an understanding of memory CD8+ T cell responses to persistent antigen restimulation is critical. However, most studies comparing memory and naive cell responses have been performed only in rapidly cleared acute infections. Herein, by comparing the responses of memory and naive CD8+ T cells to acute and chronic lymphocytic choriomeningitis virus infection, we show that memory cells dominated over naive cells and were protective when present in sufficient numbers to quickly reduce infection. In contrast, when infection was not rapidly reduced, because of high antigen load or persistence, memory cells were quickly lost, unlike naive cells. This loss of memory cells was due to a block in sustaining cell proliferation, selective regulation by the inhibitory receptor 2B4, and increased reliance on CD4+ T cell help. Thus, emphasizing the importance of designing vaccines that elicit effective CD4+ T cell help and rapidly control infection. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
23. 4-1BB Signaling Synergizes with Programmed Death Ligand 1 Blockade To Augment CD8 T Cell Responses during Chronic Viral Infection.
- Author
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Vezys, Vaiva, Penaloza-MacMaster, Pablo, Barber, Daniel L., Sang-Jun Ha, Konieczny, Bogumila, Freeman, Gordon J., Mittler, Robert S., and Ahmed, Raft
- Subjects
- *
INFECTION , *T cells , *LYMPHOCYTIC choriomeningitis , *CELL death , *APOPTOSIS - Abstract
Previous studies have identified the inhibitory role that the programmed death 1 (PD-1) pathway plays during chronic infection. Blockade of this pathway results in rescue of viral-specific CD8 T cells, as well as reduction of viral loads in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). We tested the effect of combining PD ligand 1 (PD-L1) blockade with an agonistic regimen that induces 4-1BB costimulation during chronic LCMV infection. There is a boosting effect in the rescue of LCMV-specific CD8 T cell responses after dual treatment with PD-L1 blockade and 4-1BB agonistic Abs when the amount and timing of 4-1BB costimulation are carefully controlled. When PD-L1--blocking Abs are given together with a single low dose of anti--4-1BB agonistic Abs, there is an enhanced and stable expansion of viral-specific CD8 T cells. Conversely, when blocking Abs to PD-L1 are given with a repetitive high dose of anti--4-1BB, there is an initial synergistic expansion of viral-specific CD8 T cells by day 7, followed by dramatic apoptosis by day 14. Viral control paralleled CD8 T cell kinetics after dual treatment. By day 7 posttreatment, viral titers were lower in both of the combined regimens (compared with PD-L1 blockade alone). However, whereas the high dose of anti--4-1BB plus PD-L1 blockade resulted in rebound of viral titers to original levels, the low dose of anti-4--1BB plus PD-L1 blockade resulted in a stable reduction of viral loads. These findings demonstrate the importance of carefully manipulating the balance between activating and inhibitory signals to enhance T cell responses during chronic infection. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
24. Proliferating Transitory T Cells with an Effector-like Transcriptional Signature Emerge from PD-1+ Stem-like CD8+ T Cells during Chronic Infection.
- Author
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Hudson, William H., Gensheimer, Julia, Hashimoto, Masao, Wieland, Andreas, Valanparambil, Rajesh M., Li, Peng, Lin, Jian-Xin, Konieczny, Bogumila T., Im, Se Jin, Freeman, Gordon J., Leonard, Warren J., Kissick, Haydn T., and Ahmed, Rafi
- Subjects
- *
GRANZYMES , *T cells , *LYMPHOCYTIC choriomeningitis virus , *CHEMOKINE receptors , *CELL populations , *VIRUS diseases - Abstract
T cell dysfunction is a characteristic feature of chronic viral infection and cancer. Recent studies in chronic lymphocytic choriomeningitis virus (LCMV) infection have defined a PD-1+ Tcf-1+ CD8+ T cell subset capable of self-renewal and differentiation into more terminally differentiated cells that downregulate Tcf-1 and express additional inhibitory molecules such as Tim3. Here, we demonstrated that expression of the glycoprotein CD101 divides this terminally differentiated population into two subsets. Stem-like Tcf-1+ CD8+ T cells initially differentiated into a transitory population of CD101−Tim3+ cells that later converted into CD101+ Tim3+ cells. Recently generated CD101−Tim3+ cells proliferated in vivo , contributed to viral control, and were marked by an effector-like transcriptional signature including expression of the chemokine receptor CX3CR1, pro-inflammatory cytokines, and granzyme B. PD-1 pathway blockade increased the numbers of CD101−Tim3+ CD8+ T cells, suggesting that these newly generated transitional cells play a critical role in PD-1-based immunotherapy. • CX3CR1+ CD8+ T cells are recent progeny of stem-like cells in chronic infection • CX3CR1+ cells differentiate to a dysfunctional state marked by CD101 expression • Transitory CX3CR1+ cells express effector molecules and contribute to viral control • PD-1 pathway blockade increases the number of antigen-specific transitory cells Chronic viral infection induces exhaustion of antigen-specific T cells. Hudson and colleagues define a transitory, effector-like population of CD8+ T cells that are recently generated from stem-like CD8+ T cells in chronic infection. These transitory cells contribute to viral control and are increased in number following PD-1 pathway blockade. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
25. Translation is actively regulated during the differentiation of CD8 + effector T cells.
- Author
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Araki K, Morita M, Bederman AG, Konieczny BT, Kissick HT, Sonenberg N, and Ahmed R
- Subjects
- Animals, Arenaviridae Infections genetics, Arenaviridae Infections metabolism, CD8-Positive T-Lymphocytes metabolism, Cell Differentiation genetics, Flow Cytometry, Gene Expression Regulation, Immunologic Memory immunology, Interferon-gamma immunology, Lymphocytic choriomeningitis virus, Mice, Protein Biosynthesis genetics, RNA, Messenger metabolism, Receptors, Antigen, T-Cell immunology, Reverse Transcriptase Polymerase Chain Reaction, Ribosomal Proteins genetics, Ribosomal Proteins metabolism, TOR Serine-Threonine Kinases immunology, Arenaviridae Infections immunology, CD8-Positive T-Lymphocytes immunology, Cell Differentiation immunology, Protein Biosynthesis immunology
- Abstract
Translation is a critical process in protein synthesis, but translational regulation in antigen-specific T cells in vivo has not been well defined. Here we have characterized the translatome of virus-specific CD8
+ effector T cells (Teff cells) during acute infection of mice with lymphocytic choriomeningitis virus (LCMV). Antigen-specific T cells exerted dynamic translational control of gene expression that correlated with cell proliferation and stimulation via the T cell antigen receptor (TCR). The translation of mRNAs that encode translation machinery, including ribosomal proteins, was upregulated during the T cell clonal-expansion phase, followed by inhibition of the translation of those transcripts when the CD8+ Teff cells stopped dividing just before the contraction phase. That translational suppression was more pronounced in terminal effector cells than in memory precursor cells and was regulated by antigenic stimulation and signals from the kinase mTOR. Our studies show that translation of transcripts encoding ribosomal proteins is regulated during the differentiation of CD8+ Teff cells and might have a role in fate 'decisions' involved in the formation of memory cells.- Published
- 2017
- Full Text
- View/download PDF
26. Adenovirus Serotype 5 Vaccination Results in Suboptimal CD4 T Helper 1 Responses in Mice.
- Author
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Lee J, Hashimoto M, Im SJ, Araki K, Jin HT, Davis CW, Konieczny BT, Spies GA, McElrath MJ, and Ahmed R
- Subjects
- Administration, Intravenous, Animals, Antibodies, Viral blood, Cell Differentiation immunology, Female, Glycoproteins immunology, Injections, Intramuscular, Lymphocytic Choriomeningitis blood, Lymphocytic Choriomeningitis immunology, Mice, Inbred C57BL, Viral Proteins immunology, Viral Vaccines immunology, Adenoviridae immunology, Lymphocytic Choriomeningitis prevention & control, Lymphocytic choriomeningitis virus immunology, Th1 Cells immunology, Vaccination, Viral Vaccines administration & dosage
- Abstract
Adenovirus serotype 5 (Ad5) is one of the most widely used viral vectors and is known to generate potent T cell responses. While many previous studies have characterized Ad5-induced CD8 T cell responses, there is a relative lack of detailed studies that have analyzed CD4 T cells elicited by Ad5 vaccination. Here, we immunized mice with Ad5 vectors encoding lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) and examined GP-specific CD4 T cell responses elicited by Ad5 vectors and compared them to those induced by an acute LCMV infection. In contrast to LCMV infection, where balanced CD4 T helper 1 (Th1) and T follicular helper (Tfh) responses were induced, Ad5 immunization resulted in a significantly reduced frequency of Th1 cells. CD4 T cells elicited by Ad5 vectors expressed decreased levels of Th1 markers, such as Tim3, SLAM, T-bet, and Ly6C, had smaller amounts of cytotoxic molecules like granzyme B, and produced less interferon gamma than CD4 T cells induced by LCMV infection. This defective CD4 Th1 response appeared to be intrinsic for Ad5 vectors and not a reflection of comparing a nonreplicating vector to a live viral infection, since immunization with a DNA vector expressing LCMV-GP generated efficient CD4 Th1 responses. Analysis at early time points (day 3 or 4) after immunization with Ad5 vectors revealed a defect in the expression of CD25 (interleukin-2 [IL-2] receptor alpha chain) on Ad5-elicited CD4 T cells, and administration of exogenous IL-2 following Ad5 immunization partially restored CD4 Th1 responses. These results suggest that impairment of Th1 commitment after Ad5 immunization could be due to reduced IL-2-mediated signaling. IMPORTANCE During viral infection, generating balanced responses of Th1 and Tfh cells is important to induce effective cell-mediated responses and provide optimal help for antibody responses. In this study, to investigate vaccine-induced CD4 T cell responses, we characterized CD4 T cells after immunization with Ad5 vectors expressing LCMV-GP in mice. Ad5 vectors led to altered effector differentiation of LCMV GP-specific CD4 T cells compared to that during LCMV infection. CD4 T cells following Ad5 immunization exhibited impaired Th1 lineage commitment, generating significantly decreased Th1 responses than those induced by LCMV infection. Our results suggest that suboptimal IL-2 signaling possibly plays a role in reduced Th1 development following Ad5 immunization., (Copyright © 2017 American Society for Microbiology.)
- Published
- 2017
- Full Text
- View/download PDF
27. Autophagy is essential for effector CD8(+) T cell survival and memory formation.
- Author
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Xu X, Araki K, Li S, Han JH, Ye L, Tan WG, Konieczny BT, Bruinsma MW, Martinez J, Pearce EL, Green DR, Jones DP, Virgin HW, and Ahmed R
- Subjects
- Animals, Cell Separation, Cell Survival immunology, Chromatography, Liquid, Flow Cytometry, Immunoblotting, Lymphocyte Activation immunology, Lymphocytic Choriomeningitis immunology, Mass Spectrometry, Mice, Mice, Mutant Strains, Oligonucleotide Array Sequence Analysis, Real-Time Polymerase Chain Reaction, Transduction, Genetic, Autophagy immunology, CD8-Positive T-Lymphocytes immunology, Cell Differentiation immunology, Immunologic Memory immunology
- Abstract
The importance of autophagy in the generation of memory CD8(+) T cells in vivo is not well defined. We report here that autophagy was dynamically regulated in virus-specific CD8(+) T cells during acute infection of mice with lymphocytic choriomeningitis virus. In contrast to the current paradigm, autophagy decreased in activated proliferating effector CD8(+) T cells and was then upregulated when the cells stopped dividing just before the contraction phase. Consistent with those findings, deletion of the gene encoding either of the autophagy-related molecules Atg5 or Atg7 had little to no effect on the proliferation and function of effector cells, but these autophagy-deficient effector cells had survival defects that resulted in compromised formation of memory T cells. Our studies define when autophagy is needed during effector and memory differentiation and warrant reexamination of the relationship between T cell activation and autophagy.
- Published
- 2014
- Full Text
- View/download PDF
28. Interleukin-21 is a critical cytokine for the generation of virus-specific long-lived plasma cells.
- Author
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Rasheed MA, Latner DR, Aubert RD, Gourley T, Spolski R, Davis CW, Langley WA, Ha SJ, Ye L, Sarkar S, Kalia V, Konieczny BT, Leonard WJ, and Ahmed R
- Subjects
- Animals, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Germinal Center immunology, Hemagglutination Tests, Mice, Mice, Inbred C57BL, Mice, Knockout, Neutralization Tests, Plasma Cells virology, Real-Time Polymerase Chain Reaction, Receptors, Interleukin-21 genetics, Cell Differentiation immunology, Immunity, Humoral immunology, Interleukins immunology, Plasma Cells immunology, Virus Diseases immunology
- Abstract
Long-lived plasma cells that reside in the bone marrow constitutively produce antibody in the absence of antigen and are the cellular basis of durable humoral immunity. The generation of these long-lived plasma cells depends upon a series of highly orchestrated interactions between antigen-specific CD4 T cells and B cells and the formation of germinal centers (GCs). In this study, we have examined the role of the cytokine interleukin-21 (IL-21) in regulating humoral immunity during acute viral infections. Using IL-21 receptor-deficient (IL-21R(-/-)) mice, we found that virus-specific CD4 T cells were generated after infection with lymphocytic choriomeningitis virus (LCMV) and that these CD4 T cells differentiated into T follicular helper (TFH)-like cells in the absence of IL-21 signaling. There was also no defect in the formation of GCs, although after day 15 these GCs disappeared faster in IL-21R(-/-) mice than in wild-type mice. Isotype switching and the initial LCMV-specific IgG response were normal in IL-21R(-/-) mice. However, these mice exhibited a profound defect in generating long-lived plasma cells and in sustaining antibody levels over time. Similar results were seen after infection of IL-21R(-/-) mice with vesicular stomatitis virus and influenza virus. Using chimeric mice containing wild-type or IL-21R(-/-) CD4 T cells and B cells, we showed that both B and CD4 T cells need IL-21 signaling for generating long-term humoral immunity. Taken together, our results highlight the importance of IL-21 in humoral immunity to viruses.
- Published
- 2013
- Full Text
- View/download PDF
29. Utilizing a retroviral RNAi system to investigate in vivo mTOR functions in T cells.
- Author
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Araki K and Konieczny BT
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, CD8-Positive T-Lymphocytes cytology, Carrier Proteins genetics, Carrier Proteins metabolism, Cell Differentiation, Cell Line, Disease Models, Animal, Flow Cytometry, Gene Expression Regulation, Gene Silencing immunology, Genetic Vectors, Humans, Lymphocytic Choriomeningitis genetics, Lymphocytic Choriomeningitis metabolism, Lymphocytic Choriomeningitis virology, Mice, Mice, Inbred C57BL, Regulatory-Associated Protein of mTOR, Retroviridae, Tacrolimus Binding Protein 1A genetics, Tacrolimus Binding Protein 1A metabolism, Transduction, Genetic, CD8-Positive T-Lymphocytes immunology, Gene Knockdown Techniques, Immunity, Innate genetics, RNA Interference, TOR Serine-Threonine Kinases genetics, TOR Serine-Threonine Kinases immunology
- Abstract
RNA interference (RNAi) is an intracellular mechanism for silencing gene expression utilizing short fragments of double-strand RNA that are complementary to the target messenger RNA. This gene silencing technique has now become an invaluable research tool due to its specific and strong repressive effect on a target transcript. We have recently applied a retrovirus-based RNAi system to investigate the in vivo role of the mammalian target of rapamycin (mTOR) in antigen-specific CD8 T cells, and have found that mTOR regulates memory CD8 T-cell differentiation. Here, we provide a detailed protocol for knocking down mTOR and its related molecules (raptor and FKBP12) in antigen-specific CD8 T cells. In our protocol, a mouse model of lymphocytic choriomeningitis virus infection is used, but the methods can be extended to other viral and bacterial infections as well as vaccinations. Also, the similar approach can be applied to analysis of CD4 T-cell responses.
- Published
- 2012
- Full Text
- View/download PDF
30. Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates.
- Author
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Sarkar S, Kalia V, Haining WN, Konieczny BT, Subramaniam S, and Ahmed R
- Subjects
- Animals, CD8-Positive T-Lymphocytes classification, CD8-Positive T-Lymphocytes cytology, Cell Differentiation, Cell Proliferation, Down-Regulation, Gene Expression Profiling, Granzymes biosynthesis, Interleukin-2 biosynthesis, Interleukin-7 Receptor alpha Subunit genetics, Interleukin-7 Receptor alpha Subunit metabolism, Lectins, C-Type, Lymphocytic choriomeningitis virus genetics, Lymphocytic choriomeningitis virus immunology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Oligonucleotide Array Sequence Analysis, Receptors, Immunologic genetics, Receptors, Immunologic metabolism, Receptors, Interleukin-7 genetics, Receptors, Interleukin-7 metabolism, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Immunologic Memory
- Abstract
An important question in memory development is understanding the differences between effector CD8 T cells that die versus effector cells that survive and give rise to memory cells. In this study, we provide a comprehensive phenotypic, functional, and genomic profiling of terminal effectors and memory precursors. Using killer cell lectin-like receptor G1 as a marker to distinguish these effector subsets, we found that despite their diverse cell fates, both subsets possessed remarkably similar gene expression profiles and functioned as equally potent killer cells. However, only the memory precursors were capable of making interleukin (IL) 2, thus defining a novel effector cell that was cytotoxic, expressed granzyme B, and produced inflammatory cytokines in addition to IL-2. This effector population then differentiated into long-lived protective memory T cells capable of self-renewal and rapid recall responses. Experiments to understand the signals that regulate the generation of terminal effectors versus memory precursors showed that cells that continued to receive antigenic stimulation during the later stages of infection were more likely to become terminal effectors. Importantly, curtailing antigenic stimulation toward the tail end of the acute infection enhanced the generation of memory cells. These studies support the decreasing potential model of memory differentiation and show that the duration of antigenic stimulation is a critical regulator of memory formation.
- Published
- 2008
- Full Text
- View/download PDF
31. The allograft defines the type of rejection (acute versus chronic) in the face of an established effector immune response.
- Author
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Chalasani G, Li Q, Konieczny BT, Smith-Diggs L, Wrobel B, Dai Z, Perkins DL, Baddoura FK, and Lakkis FG
- Subjects
- Acute Disease, Adoptive Transfer, Animals, Cell Adhesion Molecules biosynthesis, Cell Movement, Chemokines biosynthesis, Chronic Disease, Graft Rejection diagnosis, Mice, Mice, Inbred Strains, Reperfusion Injury, Time Factors, Transplantation, Homologous, Graft Rejection immunology, Heart Transplantation immunology, Immunity, Cellular, T-Lymphocytes
- Abstract
Transplanted organs fail due to either acute or chronic rejection. The prevailing view is that the nature or magnitude of the recipient's immune response to donor Ags determines the type of rejection. In variance with this view, we show in this study that the status of the graft itself plays a dominant role in defining the type of rejection even in the face of an established alloimmune response. Using adoptive transfer mouse models in which the graft is exposed to a constant number of effector lymphocytes, we found that newly transplanted heart allografts are rejected acutely, while healed-in allografts undergo chronic rejection. Acute rejection of healed-in allografts was largely recapitulated by subjecting the grafts to ischemia-reperfusion injury similar to that present in newly transplanted organs. Ischemia-Reperfusion injury altered the outcome of rejection by enhancing the accumulation of effector T cells within the graft. The accumulation of effector T cells in the graft was dependent on the presence of both ischemia-reperfusion injury (inflammation) and alloantigens. These findings demonstrate that the graft plays a dominant role in shaping the outcome of rejection by controlling the trafficking of effector T cells.
- Published
- 2004
- Full Text
- View/download PDF
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