Metabolic regulation by PD-1 signaling promotes long-lived quiescent CD8 T cell memory in mice
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PROVIDER: PRJNA750506 | ENA |
REPOSITORIES: ENA
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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: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 preexisting 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 bioenergetic needs of quiescent CD8 T cell memory. These results define PD-1 as a key metabolic regulator of protective T cell immunity. Furthermore, these results have potential clinical implications for preexisting CD8 T cell memory during PD-1 checkpoint blockade therapy.
| S-EPMC8896520 | biostudies-literature
Project description:CD8 effector T cells with a CD127hi KLRG1- phenotype are considered precursors to the long-lived memory pool, while KLRG1+ CD127low cells are viewed as short-lived effectors. Nevertheless, we and others have shown that a KLRG1+ CD127low population persists into the memory phase and that these T cells (termed long-lived effector cells or LLEC) display robust protective function during acute re-challenge with bacteria or viruses. Whether these T cells represent a true memory population or are instead a remnant effector cell population that failed to undergo initial contraction has remained unclear. Here, we show that LLEC from mice express a distinct phenotypic and transcriptional signature that shares characteristics of both early effectors and long-lived memory cells. Furthermore, we find that LLEC are exclusively derived from day 12 KLRG1+ effector cells. Our work challenges the concept that the KLRG1+ CD127low population is dominated by short-lived cells and shows that KLRG1 downregulation is not a prerequisite to become a long-lived protective memory T cell.
2020-08-26 | GSE152841 | GEO
Project description:KLRG1+ Memory CD8 T cells Combine Properties of Short-lived Effectors and Long-lived Memory
| PRJNA640616 | ENA
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:Memory B cells represent one of the pillar of humoral protection and are found in the circulation and secondary lymphoid organs several decades after initial pathogen or vaccine encounter. The exact cellular and biological mechanisms allowing long-term survival of quiescent cells in such a fluctuating microenvironment remain poorly understood. Assessing the true longevity of human memory B cells against common pathogens is, in most settings, hindered by the possibility for any given individual to re-encounter them during his lifetime. Smallpox, officially declared eradicated in 1980 (Fenner WHO 1988), represents one notable exception. Alongside smallpox eradication, anti-smallpox vaccination, based on the live Vaccinia virus, was progressively discontinued during the 1970s. As such, any detectable anti-vaccinia memory B cell in an individual post 2010 would likely have been generated more than 40 years ago, without any re-stimulation with the immunizing antigen during that timeframe. Anti-vaccinia antibodies serum titers remain stable in human for more than 80 years after first vaccination (Amanna NEJM 2007, PMID: 17989383), with several identified immunodominant epitopes including the envelope glycoprotein B5R (Lantto J Virol 2011, PMID: 21147924). Anti-vaccinia memory B cells have similarly been followed longitudinally in the blood for up to 65 years post vaccination (Amanna NEJM 2007, PMID: 17989383 ; Crotty JI 2003, PMID : 14607890) and, following a contraction phase taking place in the first couple of years after immunization, reach a remarkably stable plateau that last for decades at around 0.1% of total circulating IgG+ memory B cells. Functional analysis of such long-lived memory B cells, however, is still lacking. As a proxy to study long-lived memory B cells, IgG+ switched memory B cells specific for the immunodominant Vaccinia antigen B5R (B5R+ IgG+ memory B cells) were sorted and analyzed by scRNAseq from the spleen of six organ donors, collected between 2015 and 2018. For all donors, B5R+ IgG+ memory B cells were sorted alongside total IgG+ memory B cells (live IgD-CD27+IgG+CD20+CD3-CD14-CD16-) and naïve B cells (live IgD+CD27-CD38-CD24-CD20+CD3-CD14-CD16-). Single-cell mRNA sequencing was performed according to an adapted version of the SORT-seq protocol (Muraro et al., 2016, PMID: 27693023), with cDNA libraries generation, sequencing and reads alignment performed at Single Cell Discoveries (Utrecht, Netherlands).
2022-09-19 | E-MTAB-11626 | biostudies-arrayexpress
Project description:Effector CD8 T cells dedifferentiate into long-lived memory cells
| PRJNA419196 | ENA
Project description:NP-reactive murine splenic memory B cells were sorted based on the expression of the surface markers CD80 and PD-L2 AM14 tg+ X Vk8R+/- recipients of B1-8+ B cells were immunized with NP-CGG and 8 weeks later splenic EMA-, CD19+ and NP+ memory B cells were sorted based on their surface expression of CD80 and PD-L2 (DN=CD80- PDL2-, SP=CD80- PDL2+, DP=CD80+ PDL2+). 1x10E5 up to 3x10E5 cells per sample were sorted and total RNA was isolated using the RNeasy plus micro kit and cRNA was prepared using the Illumina TotalPrep RNA Amplification Kit.
2014-05-06 | E-GEOD-51604 | biostudies-arrayexpress
Project description:Immune memory cells are poised to rapidly expand and elaborate effector functions upon reinfection. However, despite heightened readiness to respond, memory cells exist in a functionally quiescent state. The paradigm is that memory cells remain inactive due to lack of TCR stimuli. Here we report a unique role of Tregs in orchestrating memory quiescence by inhibiting effector and proliferation programs through CTLA-4. Loss of Tregs resulted in activation of genome-wide transcriptional programs characteristic of potent effectors, and both developing and established memory quickly reverted to a terminally differentiated (KLRG-1hi/IL-7R±lo/GzmBhi) phenotype, with compromised metabolic fitness, longevity, polyfunctionality and protective efficacy. CTLA-4, an inhibitory receptor overexpressed on Tregs, functionally replaced Tregs in trans to rescue Treg-less memory defects and restore homeostasis of secondary mediators as well. These studies present CD28-CTLA-4-CD80/CD86 axis as a novel target to potentially accelerate vaccine-induced immunity and improve T-cell memory quality in current cancer immunotherapies proposing transient Treg-depletion. We used microarray analysis to detail the global programming of gene expression in LCMV GP33-specific CD8 T cells differentiated in the presence or absence of regulatory T cells Differentiation of memory CD8 T cells entails a progressive transition of highly activated effector program to a quiescent memory program. A key question in the field is to understand the factors that aid in the differentiation of memory cells from effector cells. It is a generally accepted paradigm that effector cells transition to a memory state by default after antigen clearance, since TCR stimuli is the key driver of effector programs in CD8 T cells. We hypothesized that the effector to memory transition of CD8 T cells involves active immunological brakes through regulatory T cells (Tregs) that allow the highly activated effector cells to convert into quiescent memory cells. To address this hypothesis, we used FoxP3-DTR mice to deplete Tregs during the window following antigen clearance, during which the effector CD8 T cells convert to long-lived memory cells. To get a deeper understanding of the global transcriptome of CD8 T cells as they transition from an effector to a memory state, we isolated and arrayed the antigen-specific CD8 T cells at day 16 post-infection that have experienced the transitional environment with and without the presence of Tregs.
2015-06-16 | E-GEOD-67593 | biostudies-arrayexpress
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