The PD-1 pathway regulates development and function of memory CD8+ T cells following respiratory viral infection
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PROVIDER: PRJNA628666 | ENA |
REPOSITORIES: ENA
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Project description:The PD-1:PD-L co-inhibitory pathway regulates dysfunctional T cells in chronic viral infection and cancer, but the role of this pathway in effector and memory responses following acute infection or vaccination remains less clear. Here we demonstrated that in the absence of signals from the PD-1 pathway, cell intrinsic alterations during initial CD8+ T cell priming resulted in excessive early CD8+ T cell expansion, but increased CD8+ T cell contraction and aberrant effector to memory CD8+ T cell transition. Overall, our studies revealed a critical and previously unappreciated role for PD-1 as an integrator of early CD8+ T cell activation signals that promoted optimal CD8+ T cell memory formation and durability. This novel PD-1 function has therapeutic implications for the generation of T cell memory during PD-1 cancer immunotherapy and modulation of the PD-1 pathway to enhance immune memory following acute infection or prophylactic vaccination. Microarrays were performed on influenza-specific CD8+ T cells isolated from the lungs of wildtype and PD-L1/L2 double knockout mice that were infected intranasally with X31-GP33. Influenza-specific CD8+ T cells were harvested at day 8 in order to determine the global program of gene expression at during the effector phase of the response to influenza to begin to dissect the role of PD-1 signaling early during effector and memory differentiation.
2020-06-30 | GSE149425 | GEO
Project description:Chronic viral infections are characterized by a state of CD8 T cell dysfunction termed exhaustion. A better understanding of the mechanisms that regulate CD8 T cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8 T cells. Here we identify a novel population of virus-specific CD8 T cells with a T follicular helper (Tfh)-like signature in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These Tfh-like CD8 T cells expressed the programmed cell death-1 (PD-1) inhibitory receptor but at the same time also expressed co-stimulatory molecules and had a gene signature that was related to CD8 T cell memory precursor cells and hematopoietic stem cells (HSC). These Tfh-like CD8 T cells acted as stem cells during chronic infection undergoing self-renewal and also differentiating into the terminally exhausted CD8 T cells that were present in both lymphoid and non-lymphoid tissues. The Tfh-like CD8 T cells were found only in lymphoid tissues and resided predominantly in the T cell zones along with naïve CD8 T cells. Interestingly, the proliferative burst after PD-1 blockade came almost exclusively from this Tfh-like CD8 T cell subset. Importantly, the transcription factor TCF1 played a cell intrinsic and essential role in the generation of Tfh-like CD8 T cells. Taken together, our study identifies Tfh-like CD8 T cells as the critical subset for maintaining the pool of virus-specific CD8 T cells during chronic infection and as the cells that proliferate after PD-1 blockade. These findings provide a better understanding of T cell exhaustion and have implications towards optimizing PD-1 directed immunotherapy. 8 samples isolated from CD8 T-cells in LCMV clone 13 GK1.5 infected mice (2 naïve, 3 CXCR5+Tim3-, 3 CXCR5-Tim3+) cells were analyzed
2016-08-02 | E-GEOD-84105 | 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 are characterized by a state of CD8 T cell dysfunction termed exhaustion. A better understanding of the mechanisms that regulate CD8 T cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8 T cells. Here we identify a novel population of virus-specific CD8 T cells with a T follicular helper (Tfh)-like signature in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These Tfh-like CD8 T cells expressed the programmed cell death-1 (PD-1) inhibitory receptor but at the same time also expressed co-stimulatory molecules and had a gene signature that was related to CD8 T cell memory precursor cells and hematopoietic stem cells (HSC). These Tfh-like CD8 T cells acted as stem cells during chronic infection undergoing self-renewal and also differentiating into the terminally exhausted CD8 T cells that were present in both lymphoid and non-lymphoid tissues. The Tfh-like CD8 T cells were found only in lymphoid tissues and resided predominantly in the T cell zones along with naïve CD8 T cells. Interestingly, the proliferative burst after PD-1 blockade came almost exclusively from this Tfh-like CD8 T cell subset. Importantly, the transcription factor TCF1 played a cell intrinsic and essential role in the generation of Tfh-like CD8 T cells. Taken together, our study identifies Tfh-like CD8 T cells as the critical subset for maintaining the pool of virus-specific CD8 T cells during chronic infection and as the cells that proliferate after PD-1 blockade. These findings provide a better understanding of T cell exhaustion and have implications towards optimizing PD-1 directed immunotherapy.
2016-08-02 | GSE84105 | GEO
Project description:Inhibitory signaling in dysfunctional CD8 T cells through the programmed cell death 1 (PD-1) axis is well established in chronic viral infections and cancers. PD-1 is also transiently induced to high concentrations during priming of acute infections and immunizations, yet its impact on the development of long-lived antigen-independent T cell memory remains unclear. In addition to its expected role in restraining clonal effector expansion, here we show that PD-1 expression on antigen-specific CD8 T cells is required for the development of a durable CD8 T cell memory pool after antigen clearance. Loss of T cell-specific PD-1 signaling led to increased contraction and a defect in antigen-independent renewal of memory CD8 T cells in response to homeostatic cytokine signals, thus resulting in attrition of the memory pool over time. Whereas exhausted CD8 T cells regain function after PD-1 checkpoint blockade during chronic viral infection, the pre-existing pool of resting functional bystander memory CD8 T cells established in response to a previously administered immunogen decreased. Metabolically, PD-1 signals were necessary for regulating the critical balance of mTOR-dependent anabolic glycolysis and fatty acid oxidation programs to meet the bioenergetics needs of quiescent memory. These results define PD-1 as a key metabolic regulator of protective T cell immunity. Further, these results have potential clinical implications for pre-existing CD8 T cell memory during PD-1 checkpoint blockade immunotherapy. We used genomewide microarrays to analyze the mRNA gene expression profile of LCMV GP33-specific effector CD8 T cells from P14 mice that were differentiated in the presence (WT) or absence of PD1 signals (PD1KO) upon in vivo infection with LCMV Armstrong.
2021-07-29 | GSE181068 | GEO
Project description:Memory CD8+ T cells are indispensable for maintaining long-term immunity against intracellular pathogens and tumors. Despite their presence in oxygen-deprived tissues of infection sites or tumors, the impact of local oxygen pressure on memory CD8+ T cells has remained largely unclear. We sought to elucidate how oxygen pressure impacted memory CD8+ T cells arising after infection with Listeria monocytogenes-OVA. Our data revealed that reduced oxygen pressure during in vitro culture switched CD8+ T cell metabolism from an OXPHOS to a glycolytic phenotype. Quantitative proteomic analysis showed that limiting oxygen conditions increased the expression of glucose transporters and components of the glycolytic pathway, while decreasing TCA cycle and mitochondrial respiratory chain proteins. The altered CD8+ T cell metabolism did not affect the expansion potential, but enhanced the granzyme B and IFN- production capacity. Memory CD8+ T cells cultured under low oxygen pressure were able to persist long-term in vivo and provided protection against bacterial rechallenge. Taken together, our study indicates that strategies of cellular immune therapy may benefit from reducing oxygen during culture to develop memory CD8+ T cells with superior effector functions .
2022-12-01 | PXD032236 | Pride
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.
2014-10-24 | GSE41869 | GEO
Project description:The primary goal was to determine the phenotype of PD-1+CD57- CD8+ T cells compared to other CD8+ memory T cells based on single cell RNA sequencing. Peripheral blood mononuclear cells (PBMCs) from control and hypertensive samples were included. Secondary analyses include comparing gene expression changes in these cells between control and hypertensive individuals.
2023-05-02 | GSE212953 | GEO
Project description:We have recently defined a novel population of PD-1+TCF1+virus-specific CD8 T cells that function as resource cells during chronic LCMV infection and provide the proliferative burst seen after PD-1 blockade. Such CD8 T cells have been found in other chronic infections and also in cancer in mice and humans. These CD8 T cells exhibit stem-like properties undergoing self-renewal and also giving rise to the terminally differentiated (exhausted) CD8 T cells. Here we compared the epigenetic signature of stem-like CD8 T cells with exhausted CD8 T cells. ATAC-seq analysis showed that stem-like CD8 T cells had a unique signature implicating activity of TCF (HMG family) and NF-κB (RHD family) members. In addition, transcription factor networks including Tcf7, Id3, and Bach2 were enriched in stem-like CD8 T cells. In contrast,exhausted CD8 T cells enriched accessible sites for ETS and Runx motifs in addition to a network encompassing Prdm1 and Il10. We also compared the epigenetic signatures of the two CD8 T-cellsubsets from chronically infected mice with effector and memory CD8 T cells generated after an acute LCMV infection. Both CD8T-cell subsets generated during chronic infection were strikingly different from CD8 T-cell subsets from acute infection. Interestingly, the stem-like CD8 T-cell subset from chronic infection, despite sharing key functional properties with memory CD8 T cells,had a very distinct epigenetic program. These results show that the chronic stem-like CD8 T-cell program represents a specific adaptation of the T-cell response to persistent antigenic stimulation.
2019-06-15 | GSE132110 | GEO
Project description:To test whether PD-1 exerts genome-wide gene expression changes in TCM-phenotype CD8 cells, we performed transcriptome analysis on TCM-phenotype CD8 cell subpopulations derived from 7-month old PD-1 KO and WT spleens.
2013-05-06 | E-MTAB-1569 | biostudies-arrayexpress