Metabolic exhaustion of T cells in chronic infection is mediated by inhibitory receptor PD-1 and T cell receptor dependent transcription factor IRF4
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE84820 | GEO | 2018/01/01
SECONDARY ACCESSION(S): PRJNA335368
REPOSITORIES: GEO
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Project description:CD8+ T cells in chronic viral infections like HIV develop functional defects such as loss of IL-2 secretion and decreased proliferative potential that are collectively termed exhaustion1. Exhausted T cells express increased levels of multiple inhibitory receptors, such as Programmed Death 1 (PD-1). PD-1 inhibition contributes to impaired virus-specific T cell function in chronic infection because antibody-mediated blockade of its ligand, Programmed Death Ligand 1 (PD-L1) is sufficient to improve T cell function and reduce viral replication in animal models. Reversing PD-1 inhibition is therefore an attractive therapeutic target, but the cellular mechanisms by which PD-1 ligation results in T cell inhibition are not fully understood. PD-1 is thought to limit T cell activation by attenuating T cell receptor (TCR) signaling. It is not known whether PD-1 ligation also acts by upregulating genes in exhausted T cells that impair their function. Here, we analyzed gene-expression profiles from HIV-specific CD8+ T cells in patients with HIV and show that PD-1 coordinately upregulates a program of genes in exhausted CD8+ T cells from humans and mice. This program includes upregulation of basic leucine transcription factor, ATF-like (BATF), a transcription factor in the AP-1 family. Enforced expression of BATF was sufficient to impair T cell proliferation and cytokine secretion, while BATF knockdown reduced PD-1 inhibition. Silencing BATF in CD4+ and CD8+ T cells from chronic viremic patients rescued HIV-specific T cell function. Thus inhibitory receptors can cause T cell exhaustion by upregulating genes â such as BATF â that inhibit T cell function. PD-1 expressing Jurkat cells were cultured for 18 hours with beads coated with antibodies to CD3 and CD28, with our without an antibody to PD-1.
2010-10-03 | E-GEOD-24026 | biostudies-arrayexpress
Project description:CD8+ T cells in chronic viral infections like HIV develop functional defects such as loss of IL-2 secretion and decreased proliferative potential that are collectively termed exhaustion1. Exhausted T cells express increased levels of multiple inhibitory receptors, such as Programmed Death 1 (PD-1). PD-1 inhibition contributes to impaired virus-specific T cell function in chronic infection because antibody-mediated blockade of its ligand, Programmed Death Ligand 1 (PD-L1) is sufficient to improve T cell function and reduce viral replication in animal models. Reversing PD-1 inhibition is therefore an attractive therapeutic target, but the cellular mechanisms by which PD-1 ligation results in T cell inhibition are not fully understood. PD-1 is thought to limit T cell activation by attenuating T cell receptor (TCR) signaling. It is not known whether PD-1 ligation also acts by upregulating genes in exhausted T cells that impair their function. Here, we analyzed gene-expression profiles from HIV-specific CD8+ T cells in patients with HIV and show that PD-1 coordinately upregulates a program of genes in exhausted CD8+ T cells from humans and mice. This program includes upregulation of basic leucine transcription factor, ATF-like (BATF), a transcription factor in the AP-1 family. Enforced expression of BATF was sufficient to impair T cell proliferation and cytokine secretion, while BATF knockdown reduced PD-1 inhibition. Silencing BATF in CD4+ and CD8+ T cells from chronic viremic patients rescued HIV-specific T cell function. Thus inhibitory receptors can cause T cell exhaustion by upregulating genes â such as BATF â that inhibit T cell function. We sorted HIV-specific CD8+ T cells from 18 progressors and 24 controllers, cohorts with a two-log difference in mean viral load
2010-10-03 | E-GEOD-24081 | biostudies-arrayexpress
Project description:During acute viral infections, naïve CD8+ T cells differentiate into effector CD8+ T cells and, after viral control, into memory CD8+ T cells. Memory CD8+ T cells are highly functional, proliferate rapidly upon reinfection and persist long-term without antigen. In contrast, during chronic infections, CD8+ T cells become “exhausted” and have poor effector function, express multiple inhibitory receptors, possess low proliferative capacity, and cannot persist without antigen. Exhuasted CD8+ T cells can be further segregated by their expression of the inhibitory cell surface receptor PD-1. We performed transcriptional profiling on both PD-1 High and PD-1 Intermediate H2-Db GP33-specific CD8+ T cells. H2-Db GP33-specific CD8+ T cells were sorted from C57BL/6 mice 30 days p.i. with LCMV clone 13. These cells were then segregated by their expression of the inhibitory cell surface receptor PD-1 into PD-1 High and PD-1 Intermediate subpopulations. We performed transcriptional profiling on these subpopulations.
2014-10-24 | E-GEOD-41869 | biostudies-arrayexpress
Project description:Chronic viral infections and tumours are associated with CD8+ T cell exhaustion, which is characterized by high expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and impaired effector function. Understanding the molecular regulation of T cell exhaustion is critical for the development of new immunotherapies. Chronically activated T cells are maintained by precursors of exhausted T (TPEX) cells that express the transcription factor TCF1, self-renew and give rise to TCF-1– exhausted effector T (TEX) cells; this process is currently, however, poorly understood. Here, we reveal that TPEX cells are heterogenous and contain a population of CD62L+ stem-like exhausted T cells that selectively preserve long-term self-renewal capacity and multipotency of antigen-specific T cells during chronic infection. Furthermore, we show that the transcription factor c-Myb is essential for the development of CD62L+ TPEX cells, self-renewal of TPEX cells and the induction of key features of T cell exhaustion. Consequently, Myb-deficient CD8+ T cells show uninhibited cytokine production resulting in fatal immunopathology in response to chronic but not acute LCMV infection and fail to be maintained long-term. Finally, we show that c-Myb-dependent CD62L+ TPEX cells exclusively mediate T cell proliferation during PD-1 checkpoint inhibition and show enhanced antiviral properties, making them attractive targets for new immunotherapeutic strategies. Thus, our findings identify CD62L+ TPEX cells as central to the maintenance of exhausted T cell responses and reveal c-Myb as a key transcriptional orchestrator that combines two central aspects of T cell exhaustion, limitation of T cell function and long-term maintenance during chronic infection.
2022-08-22 | GSE203575 | GEO
Project description:Chronic viral infections and tumours are associated with CD8+ T cell exhaustion, which is characterized by high expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and impaired effector function. Understanding the molecular regulation of T cell exhaustion is critical for the development of new immunotherapies. Chronically activated T cells are maintained by precursors of exhausted T (TPEX) cells that express the transcription factor TCF1, self-renew and give rise to TCF-1– exhausted effector T (TEX) cells; this process is currently, however, poorly understood. Here, we reveal that TPEX cells are heterogenous and contain a population of CD62L+ stem-like exhausted T cells that selectively preserve long-term self-renewal capacity and multipotency of antigen-specific T cells during chronic infection. Furthermore, we show that the transcription factor c-Myb is essential for the development of CD62L+ TPEX cells, self-renewal of TPEX cells and the induction of key features of T cell exhaustion. Consequently, Myb-deficient CD8+ T cells show uninhibited cytokine production resulting in fatal immunopathology in response to chronic but not acute LCMV infection and fail to be maintained long-term. Finally, we show that c-Myb-dependent CD62L+ TPEX cells exclusively mediate T cell proliferation during PD-1 checkpoint inhibition and show enhanced antiviral properties, making them attractive targets for new immunotherapeutic strategies. Thus, our findings identify CD62L+ TPEX cells as central to the maintenance of exhausted T cell responses and reveal c-Myb as a key transcriptional orchestrator that combines two central aspects of T cell exhaustion, limitation of T cell function and long-term maintenance during chronic infection.
2022-08-17 | GSE188526 | GEO
Project description:Chronic viral infections and tumours are associated with CD8+ T cell exhaustion, which is characterized by high expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and impaired effector function. Understanding the molecular regulation of T cell exhaustion is critical for the development of new immunotherapies. Chronically activated T cells are maintained by precursors of exhausted T (TPEX) cells that express the transcription factor TCF1, self-renew and give rise to TCF-1– exhausted effector T (TEX) cells; this process is currently, however, poorly understood. Here, we reveal that TPEX cells are heterogenous and contain a population of CD62L+ stem-like exhausted T cells that selectively preserve long-term self-renewal capacity and multipotency of antigen-specific T cells during chronic infection. Furthermore, we show that the transcription factor c-Myb is essential for the development of CD62L+ TPEX cells, self-renewal of TPEX cells and the induction of key features of T cell exhaustion. Consequently, Myb-deficient CD8+ T cells show uninhibited cytokine production resulting in fatal immunopathology in response to chronic but not acute LCMV infection and fail to be maintained long-term. Finally, we show that c-Myb-dependent CD62L+ TPEX cells exclusively mediate T cell proliferation during PD-1 checkpoint inhibition and show enhanced antiviral properties, making them attractive targets for new immunotherapeutic strategies. Thus, our findings identify CD62L+ TPEX cells as central to the maintenance of exhausted T cell responses and reveal c-Myb as a key transcriptional orchestrator that combines two central aspects of T cell exhaustion, limitation of T cell function and long-term maintenance during chronic infection.
2022-08-22 | GSE199839 | GEO
Project description:CD4+ T cell help is critical for optimal CD8+ T cell expansion after priming in many experimental systems. However, a role for CD4+ T cells in regulating the initial steps of CD8+ T cell effector differentiation is not well established. Here we demonstrate that absence of CD4+ T cells at the time of replication-incompetent adenovirus vector immunization of C57BL/6 mice led to immediate CD8+ T cell dysfunction characteristic of exhaustion at the first detectable timepoints as well as impaired expansion of antigen-specific CD8+ T cells. The absence of CD4+ T cell help resulted in antigen-specific CD8+ T cells that had reduced ex vivo cytotoxicity and decreased capacity to produce IFN-γ and TNF-α. CD8+ T cells primed in the absence of CD4+ T cells expressed elevated levels of the inhibitory receptors PD-1, LAG-3, and Tim-3, and these cells exhibited transcriptomic exhaustion profiles by gene set enrichment analysis. This dysfunctional state was imprinted within 3 days of immunization and could not be reversed by provision of CD4+ T cell help after priming. Partial rescue of unhelped CD8+ T cell expansion and effector differentiation could be achieved by PD-1 pathway blockade or recombinant IL-2 administration. This study identifies a novel, previously undescribed role of CD4+ T cells to prevent immediate dysfunction and features of exhaustion in CD8+ T cells following antigen priming. Splenic AL11-specific CD8 T cells from mice immunized with Ad5HVR48(1-7)-SIV Gag and treated with anti-CD4 antibody or not were purified by FACS on day 14 post-immunization
2016-07-01 | E-GEOD-73001 | biostudies-arrayexpress
Project description:The growing tumor avoids recognition and destruction by immune system. During continuous stimulation of tumor infiltrating lymphocytes (TILs) by tumor, TILs become functionally exhausted. Thus, they become unable to kill tumor cells and to produce some cytokines, and lose their ability to proliferate. It collectively results in the immune escape of cancer cells. Here, we show that breast cancer cells expressing PD-L1 can accelerate exhaustion of persistently activated human effector CD4+ T cells, manifesting in high PD-1 and PD-L1 expression level on cell surface, decreased glucose metabolism genes, strong downregulation of SWI/SNF chromatin remodeling complex subunits and p21 cell cycle inhibitor upregulation. This results in inhibition of T cell proliferation and reduction of T cells number. The RNAseq analysis on exhausted CD4+ T cells indicated strong overexpression of IDO1 and genes encoding pro-inflammatory cytokines and chemokines. The PD-L1 overexpression was also observed in CD4+ T cells after co-cultivation with other cell line overexpressing PD-L1 that suggested the existence of general mechanism of CD4+ T cell exhaustion induced by cancer cells. The ChIP analysis on PD-L1 promoter region indicated that the strong BRM recruitment in control CD4+ T cells is replaced by BRG1 and EZH2 in CD4+ T cells strongly exhausted by cancer cells. These findings suggest that such epi-drugs as EZH2 inhibitors may be used as immunomodulators in cancer treatment.
2022-02-17 | PXD026447 | Pride
Project description:CD8+ T cells in chronic viral infections like HIV develop functional defects such as loss of IL-2 secretion and decreased proliferative potential that are collectively termed exhaustion1. Exhausted T cells express increased levels of multiple inhibitory receptors, such as Programmed Death 1 (PD-1). PD-1 inhibition contributes to impaired virus-specific T cell function in chronic infection because antibody-mediated blockade of its ligand, Programmed Death Ligand 1 (PD-L1) is sufficient to improve T cell function and reduce viral replication in animal models. Reversing PD-1 inhibition is therefore an attractive therapeutic target, but the cellular mechanisms by which PD-1 ligation results in T cell inhibition are not fully understood. PD-1 is thought to limit T cell activation by attenuating T cell receptor (TCR) signaling. It is not known whether PD-1 ligation also acts by upregulating genes in exhausted T cells that impair their function. Here, we analyzed gene-expression profiles from HIV-specific CD8+ T cells in patients with HIV and show that PD-1 coordinately upregulates a program of genes in exhausted CD8+ T cells from humans and mice. This program includes upregulation of basic leucine transcription factor, ATF-like (BATF), a transcription factor in the AP-1 family. Enforced expression of BATF was sufficient to impair T cell proliferation and cytokine secretion, while BATF knockdown reduced PD-1 inhibition. Silencing BATF in CD4+ and CD8+ T cells from chronic viremic patients rescued HIV-specific T cell function. Thus inhibitory receptors can cause T cell exhaustion by upregulating genes – such as BATF – that inhibit T cell function.
2010-10-03 | GSE24081 | GEO
Project description:CD8+ T cells in chronic viral infections like HIV develop functional defects such as loss of IL-2 secretion and decreased proliferative potential that are collectively termed exhaustion1. Exhausted T cells express increased levels of multiple inhibitory receptors, such as Programmed Death 1 (PD-1). PD-1 inhibition contributes to impaired virus-specific T cell function in chronic infection because antibody-mediated blockade of its ligand, Programmed Death Ligand 1 (PD-L1) is sufficient to improve T cell function and reduce viral replication in animal models. Reversing PD-1 inhibition is therefore an attractive therapeutic target, but the cellular mechanisms by which PD-1 ligation results in T cell inhibition are not fully understood. PD-1 is thought to limit T cell activation by attenuating T cell receptor (TCR) signaling. It is not known whether PD-1 ligation also acts by upregulating genes in exhausted T cells that impair their function. Here, we analyzed gene-expression profiles from HIV-specific CD8+ T cells in patients with HIV and show that PD-1 coordinately upregulates a program of genes in exhausted CD8+ T cells from humans and mice. This program includes upregulation of basic leucine transcription factor, ATF-like (BATF), a transcription factor in the AP-1 family. Enforced expression of BATF was sufficient to impair T cell proliferation and cytokine secretion, while BATF knockdown reduced PD-1 inhibition. Silencing BATF in CD4+ and CD8+ T cells from chronic viremic patients rescued HIV-specific T cell function. Thus inhibitory receptors can cause T cell exhaustion by upregulating genes – such as BATF – that inhibit T cell function.
2010-10-03 | GSE24026 | GEO