Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA261548 | ENA |
REPOSITORIES: ENA
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Project description:Memory CD8+ T cells are an essential component of protective immunity. Signaling via mechanistic target of rapamycin (mTOR) has been implicated in the regulation of the differentiation of effector and memory T cells. However, little is understood about the mechanisms that control mTOR activity, or the effector pathways regulated by mTOR, in this process. We describe here that tuberous sclerosis 1 (Tsc1), a regulator of mTOR signaling, plays a crucial role in promoting the differentiation and function of memory CD8+ T cells in response to Listeria monocytogenes infection. Mice with specific deletion of Tsc1 in antigen-experienced CD8+ T cells evoked normal effector responses, but were markedly impaired in the generation of memory T cells and their recall responses to antigen re-exposure in a cell-intrinsic manner. Tsc1 deficiency suppressed the generation of memory-precursor effector cells (MPECs) while promoting short-lived effector cell (SLEC) differentiation. Functional genomic analysis indicated that Tsc1 coordinated gene expression programs underlying immune function, transcriptional regulation and cell metabolism. Furthermore, Tsc1 deletion led to excessive mTORC1 activity and dysregulated cellular metabolism including glycolytic and oxidative metabolism. These findings establish a Tsc1-mediated checkpoint in linking immune signaling and cell metabolism to orchestrate memory CD8+ T cell development and function. We used microarrays to explore the gene expression profiles differentially expressed in OVA-specific CD8+ T-cells from wild-type (WT; Tsc1-fl/fl and cre-negative) and Tsc1-/- (Tsc1-fl/fl and Granzyme B-cre-positive) mice
2014-09-20 | E-GEOD-61591 | biostudies-arrayexpress
Project description:Memory CD8+ T cells are an essential component of protective immunity. Signaling via mechanistic target of rapamycin (mTOR) has been implicated in the regulation of the differentiation of effector and memory T cells. However, little is understood about the mechanisms that control mTOR activity, or the effector pathways regulated by mTOR, in this process. We describe here that tuberous sclerosis 1 (Tsc1), a regulator of mTOR signaling, plays a crucial role in promoting the differentiation and function of memory CD8+ T cells in response to Listeria monocytogenes infection. Mice with specific deletion of Tsc1 in antigen-experienced CD8+ T cells evoked normal effector responses, but were markedly impaired in the generation of memory T cells and their recall responses to antigen re-exposure in a cell-intrinsic manner. Tsc1 deficiency suppressed the generation of memory-precursor effector cells (MPECs) while promoting short-lived effector cell (SLEC) differentiation. Functional genomic analysis indicated that Tsc1 coordinated gene expression programs underlying immune function, transcriptional regulation and cell metabolism. Furthermore, Tsc1 deletion led to excessive mTORC1 activity and dysregulated cellular metabolism including glycolytic and oxidative metabolism. These findings establish a Tsc1-mediated checkpoint in linking immune signaling and cell metabolism to orchestrate memory CD8+ T cell development and function.
2014-09-20 | GSE61591 | GEO
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:CD8+ T cells provide protection from infection and tumor growth, and many current immunotherapies target molecules that enhance CD8+ T cell function and differentiation. The transcriptional programs orchestrating CD8+ T cell differentiation in response to infection has been described, but the changes in spatial chromatin organization accompanying effector and memory CD8+ T cell differentiation is unknown, despite research showing the importance of long-range chromatin interactions for transcriptional regulation in various cell types. Here, we studied how genome organization is integrated with CD8+ T cell differentiation and investigated the role of CTCF, a key factor that regulates genome organization through blocking or facilitating chromatin interactions, in regulating CD8+ T cell fates. We observed T cell subset-specific changes in chromatin organization and CTCF binding, and revealed weak-affinity CTCF binding is needed to promote terminal differentiation of CD8+ T cells by coordinating chromatin interactions that regulate transcriptional programs driving CD8+ T cell differentiation.
2023-04-21 | GSE205081 | GEO
Project description:CD8+ T cells provide protection from infection and tumor growth, and many current immunotherapies target molecules that enhance CD8+ T cell function and differentiation. The transcriptional programs orchestrating CD8+ T cell differentiation in response to infection has been described, but the changes in spatial chromatin organization accompanying effector and memory CD8+ T cell differentiation is unknown, despite research showing the importance of long-range chromatin interactions for transcriptional regulation in various cell types. Here, we studied how genome organization is integrated with CD8+ T cell differentiation and investigated the role of CTCF, a key factor that regulates genome organization through blocking or facilitating chromatin interactions, in regulating CD8+ T cell fates. We observed T cell subset-specific changes in chromatin organization and CTCF binding, and revealed weak-affinity CTCF binding is needed to promote terminal differentiation of CD8+ T cells by coordinating chromatin interactions that regulate transcriptional programs driving CD8+ T cell differentiation.
2023-04-21 | GSE205079 | GEO
Project description:CD8+ T cells provide protection from infection and tumor growth, and many current immunotherapies target molecules that enhance CD8+ T cell function and differentiation. The transcriptional programs orchestrating CD8+ T cell differentiation in response to infection has been described, but the changes in spatial chromatin organization accompanying effector and memory CD8+ T cell differentiation is unknown, despite research showing the importance of long-range chromatin interactions for transcriptional regulation in various cell types. Here, we studied how genome organization is integrated with CD8+ T cell differentiation and investigated the role of CTCF, a key factor that regulates genome organization through blocking or facilitating chromatin interactions, in regulating CD8+ T cell fates. We observed T cell subset-specific changes in chromatin organization and CTCF binding, and revealed weak-affinity CTCF binding is needed to promote terminal differentiation of CD8+ T cells by coordinating chromatin interactions that regulate transcriptional programs driving CD8+ T cell differentiation.
2023-04-21 | GSE205077 | GEO
Project description:CD8+ T cells provide protection from infection and tumor growth, and many current immunotherapies target molecules that enhance CD8+ T cell function and differentiation. The transcriptional programs orchestrating CD8+ T cell differentiation in response to infection has been described, but the changes in spatial chromatin organization accompanying effector and memory CD8+ T cell differentiation is unknown, despite research showing the importance of long-range chromatin interactions for transcriptional regulation in various cell types. Here, we studied how genome organization is integrated with CD8+ T cell differentiation and investigated the role of CTCF, a key factor that regulates genome organization through blocking or facilitating chromatin interactions, in regulating CD8+ T cell fates. We observed T cell subset-specific changes in chromatin organization and CTCF binding, and revealed weak-affinity CTCF binding is needed to promote terminal differentiation of CD8+ T cells by coordinating chromatin interactions that regulate transcriptional programs driving CD8+ T cell differentiation.
2023-04-21 | GSE205076 | GEO
Project description:Metabolic fitness of T cells is crucial for immune responses against infections and tumorigenesis. Both the T cell receptor (TCR) signal and environmental cues contribute to the induction of T cell metabolic reprogramming, but the underlying mechanism is incompletely understood. Here we identified the E3 ubiquitin ligase Peli1 as an important regulator of T cell metabolism and antitumor immunity. Peli1 ablation profoundly promotes tumor rejection, associated with increased tumor-infiltrating CD4 and CD8 T cells. The Peli1-deficient T cells display markedly stronger metabolic activities, particularly glycolysis, than wildtype T cells. Peli1 controls the activation of a metabolic kinase, mTORC1, stimulated by both the TCR signal and growth factors, and this function of Peli1 is mediated through regulation of the mTORC1-inhibitory proteins, TSC1 and TSC2. Peli1 mediates non-degradative ubiquitination of TSC1, thereby promoting TSC1-TSC2 dimerization and TSC2 stabilization. These results establish Peli1 as an important regulator of T cell metabolism and antitumor immunity and suggest a novel mechanism that controls mTORC1 activation.
2020-11-23 | PXD020734 | Pride
Project description:The formation of antigen-specific memory CD8+ T cells is one of the most important features of the adaptative immune system, allowing the establishment of long-term protection against secondary infections. Although emerging evidence suggests that metabolic reprogramming is crucial for memory T cell differentiation and survival, the underlying mechanisms that drive metabolic rewiring needed for memory T cells remain unclear. Here, we found that the nuclear receptor peroxisome proliferator-activated receptor-beta/delta (PPARβ/δ) was upregulated to instruct the metabolic reprogramming, including downregulation of aerobic glycolysis and the promotion of oxidative metabolism and fatty acid oxidation, that occurs during the transition toward the establishment of central memory CD8+ T cells. Mechanistically, the exposure to interleukin-15 (IL-15) and expression of T cell factor 1 (TCF1) could coordinately activated the PPARβ/δ pathway during acute viral infection and chronic antigen exposure contexts, counteracting apoptosis induced by antigen clearance and metabolic stress. Together, our work indicates that PPARβ/δ is a master metabolic regulator orchestrating the metabolic reprogramming required for the establishment of a metabolic profile favorable for T cells longevity.
2024-08-23 | GSE268419 | GEO
Project description:The formation of antigen-specific memory CD8+ T cells is one of the most important features of the adaptative immune system, allowing the establishment of long-term protection against secondary infections. Although emerging evidence suggests that metabolic reprogramming is crucial for memory T cell differentiation and survival, the underlying mechanisms that drive metabolic rewiring needed for memory T cells remain unclear. Here, we found that the nuclear receptor peroxisome proliferator-activated receptor-beta/delta (PPARβ/δ) was upregulated to instruct the metabolic reprogramming, including downregulation of aerobic glycolysis and the promotion of oxidative metabolism and fatty acid oxidation, that occurs during the transition toward the establishment of central memory CD8+ T cells. Mechanistically, the exposure to interleukin-15 (IL-15) and expression of T cell factor 1 (TCF1) could coordinately activated the PPARβ/δ pathway during acute viral infection and chronic antigen exposure contexts, counteracting apoptosis induced by antigen clearance and metabolic stress. Together, our work indicates that PPARβ/δ is a master metabolic regulator orchestrating the metabolic reprogramming required for the establishment of a metabolic profile favorable for T cells longevity.
2024-08-23 | GSE264017 | GEO