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FOXP3 protects conventional human T cells from premature restimulation-induced cell death.

ABSTRACT: The adaptive immune response relies on specific apoptotic programs to maintain homeostasis. Conventional effector T cell (Tcon) expansion is constrained by both forkhead box P3 (FOXP3)⁺-regulatory T cells (Tregs) and restimulation-induced cell death (RICD), a propriocidal apoptosis pathway triggered by repeated stimulation through the T-cell receptor (TCR). Constitutive FOXP3 expression protects Tregs from RICD by suppressing SLAM-associated protein (SAP), a key adaptor protein that amplifies TCR signaling strength. The role of transient FOXP3 induction in activated human CD4 and CD8 Tcons remains unresolved, but its expression is inversely correlated with acquired RICD sensitivity. Here, we describe a novel role for FOXP3 in protecting human Tcons from premature RICD during expansion. Unlike FOXP3-mediated protection from RICD in Tregs, FOXP3 protects Tcons through a distinct mechanism requiring de novo transcription that does not require SAP suppression. Transcriptome profiling and functional analyses of expanding Tcons revealed that FOXP3 enhances expression of the SLAM family receptor CD48, which in turn sustains basal autophagy and suppresses pro-apoptotic p53 signaling. Both CD48 and FOXP3 expression reduced p53 accumulation upon TCR restimulation. Furthermore, silencing FOXP3 expression or blocking CD48 decreased the mitochondrial membrane potential in expanding Tcons with a concomitant reduction in basal autophagy. Our findings suggest that FOXP3 governs a distinct transcriptional program in early-stage effector Tcons that maintains RICD resistance via CD48-dependent protective autophagy and p53 suppression.

SUBMITTER: Voss K

PROVIDER: S-EPMC7852538 | biostudies-literature |

REPOSITORIES: biostudies-literature

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FOXP3 protects conventional human T cells from premature restimulation-induced cell death

Project description:Transcriptome profiling and functional analyses on expanding Tcons revealed that FOXP3 enhances expression of the SLAM family receptor CD48, which in turn sustains basal autophagy and suppresses pro-apoptotic p53 signaling. Our findings suggest that FOXP3 governs a distinct transcriptional program in early-stage effector Tcons that maintains RICD resistance via CD48-dependent protective autophagy and p53 suppression.

2019-12-15 | GSE138272 | GEO

FOXP3 protects conventional human T cells from premature restimulation-induced cell death

Project description:FOXP3 protects conventional human T cells from premature restimulation-induced cell death

| PRJNA575256 | ENA

Fatty Acid Synthase Contributes to Restimulation-Induced Cell Death of Human CD4 T Cells.

Project description:Restimulation-induced cell death (RICD) is an apoptotic pathway triggered in activated effector T cells after T cell receptor (TCR) re-engagement. RICD operates at the peak of the immune response to ensure T cell expansion remains in check to maintain immune homeostasis. Understanding the biochemical regulation of RICD sensitivity may provide strategies for tuning the magnitude of an effector T cell response. Metabolic reprogramming in activated T cells is not only critical for T cell differentiation and effector functions, but also influences apoptosis sensitivity. We previously demonstrated that aerobic glycolysis correlates with optimum RICD sensitivity in human effector CD8 T cells. However, metabolic programming in CD4 T cells has not been investigated in this context. We employed a pharmacological approach to explore the effects of fatty acid and glycolytic metabolism on RICD sensitivity in primary human CD4 T cells. Blockade of fatty acid synthase (FASN) with the compound C75 significantly protected CD4 effector T cells from RICD, suggesting that fatty acid biosynthesis contributes to RICD sensitivity. Interestingly, sphingolipid synthesis and fatty acid oxidation (FAO) were dispensable for RICD. Disruption of glycolysis did not protect CD4 T cells from RICD unless glyceraldehyde-3-phosphate dehydrogenase (GAPDH) enzymatic activity was targeted specifically, highlighting important differences in the metabolic control of RICD in effector CD4 vs. CD8 T cell populations. Moreover, C75 treatment protected effector CD4 T cells derived from naïve, effector memory, and central memory T cell subsets. Decreased RICD in C75-treated CD4 T cells correlated with markedly reduced FAS ligand (FASL) induction and a Th2-skewed phenotype, consistent with RICD-resistant CD4 T cells. These findings highlight FASN as a critical metabolic potentiator of RICD in human effector CD4 T cells.

| S-EPMC6803432 | biostudies-literature

CD48-dependent protective autophagy in conventional human T cells promotes restimulation-induced cell death resistance

2019-12-15 | GSE137931 | GEO

Sensitivity to Restimulation-Induced Cell Death Is Linked to Glycolytic Metabolism in Human T Cells.

Project description:Restimulation-induced cell death (RICD) regulates immune responses by restraining effector T cell expansion and limiting nonspecific damage to the host. RICD is triggered by re-engagement of the TCR on a cycling effector T cell, resulting in apoptosis. It remains unclear how RICD sensitivity is calibrated in T cells derived from different individuals or subsets. In this study we show that aerobic glycolysis strongly correlates with RICD sensitivity in human CD8+ effector T cells. Reducing glycolytic activity or glucose availability rendered effector T cells significantly less sensitive to RICD. We found that active glycolysis specifically facilitates the induction of proapoptotic Fas ligand upon TCR restimulation, accounting for enhanced RICD sensitivity in highly glycolytic T cells. Collectively, these data indicate that RICD susceptibility is linked to metabolic reprogramming, and that switching back to metabolic quiescence may help shield T cells from RICD as they transition into the memory pool.

| S-EPMC5310646 | biostudies-literature

MANF protects human pancreatic beta cells against stress-induced cell death.

Project description:Aims/hypothesisThere is a great need to identify factors that could protect pancreatic beta cells against apoptosis or stimulate their replication and thus prevent or reverse the development of diabetes. One potential candidate is mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum (ER) stress inducible protein. Manf knockout mice used as a model of diabetes develop the condition because of increased apoptosis and reduced proliferation of beta cells, apparently related to ER stress. Given this novel association between MANF and beta cell death, we studied the potential of MANF to protect human beta cells against experimentally induced ER stress.MethodsPrimary human islets were challenged with proinflammatory cytokines, with or without MANF. Cell viability was analysed and global transcriptomic analysis performed. Results were further validated using the human beta cell line EndoC-βH1.ResultsThere was increased expression and secretion of MANF in human beta cells in response to cytokines. Addition of recombinant human MANF reduced cytokine-induced cell death by 38% in human islets (p < 0.05). MANF knockdown in EndoC-βH1 cells led to increased ER stress after cytokine challenge. Mechanistic studies showed that the protective effect of MANF was associated with repression of the NF-κB signalling pathway and amelioration of ER stress. MANF also increased the proliferation of primary human beta cells twofold when TGF-β signalling was inhibited (p < 0.01).Conclusions/interpretationOur studies show that exogenous MANF protein can provide protection to human beta cells against death induced by inflammatory stress. The antiapoptotic and mitogenic properties of MANF make it a potential therapeutic agent for beta cell protection.

| S-EPMC6133171 | biostudies-literature

Critical role for BIM in T cell receptor restimulation-induced death.

Project description:BackgroundUpon repeated or chronic antigen stimulation, activated T cells undergo a T cell receptor (TCR)-triggered propriocidal cell death important for governing the intensity of immune responses. This is thought to be chiefly mediated by an extrinsic signal through the Fas-FasL pathway. However, we observed that TCR restimulation still potently induced apoptosis when this interaction was blocked, or genetically impaired in T cells derived from autoimmune lymphoproliferative syndrome (ALPS) patients, prompting us to examine Fas-independent, intrinsic signals.ResultsUpon TCR restimulation, we specifically noted a marked increase in the expression of BIM, a pro-apoptotic Bcl-2 family protein known to mediate lymphocyte apoptosis induced by cytokine withdrawal. In fact, T cells from an ALPS type IV patient in which BIM expression is suppressed were more resistant to restimulation-induced death. Strikingly, knockdown of BIM expression rescued normal T cells from TCR-induced death to as great an extent as Fas disruption.ConclusionOur data implicates BIM as a critical mediator of apoptosis induced by restimulation as well as growth cytokine withdrawal. These findings suggest an important role for BIM in eliminating activated T cells even when IL-2 is abundant, working in conjunction with Fas to eliminate chronically stimulated T cells and maintain immune homeostasis.ReviewersThis article was reviewed by Dr. Wendy Davidson (nominated by Dr. David Scott), Dr. Mark Williams (nominated by Dr. Neil Greenspan), and Dr. Laurence C. Eisenlohr.

| S-EPMC2529272 | biostudies-literature

CD48-dependent protective autophagy in conventional human T cells promotes restimulation-induced cell death resistance

Project description:CD48-dependent protective autophagy in conventional human T cells promotes restimulation-induced cell death resistance

| PRJNA573899 | ENA

IRX-2, a novel immunotherapeutic, protects human T cells from tumor-induced cell death.

Project description:IRX-2 is a cytokine-based biologic agent that has the potential to enhance antitumor immune responses. We investigated whether IRX-2 can protect T cells from tumor-induced apoptosis. Tumor-derived microvesicles (MV) expressing FasL were purified from supernatants of tumor cells and incubated with activated CD8(+) T cells. MV induced significant CD8(+) T-cell apoptosis, as evidenced by Annexin binding (64.4+/-6.4%), caspase activation (58.1+/-7.6%), a loss of mitochondrial membrane potential (82.9+/-3.9%) and DNA fragmentation. T-cell pretreatment with IRX-2 prevented apoptosis. IRX-2-mediated cytoprotection was dose and time dependent and was comparable to effects of IL-2, IL-7 or IL-15. IRX-2 prevented MV-induced downregulation of JAK3 and TCRzeta chain and induced STAT5 activation in T cells. IRX-2 prevented MV-induced Bax and Bim upregulation (P<0.005-0.05), prevented cytochrome c release and Bid cleavage, and concurrently restored the expression of Bcl-2, Bcl-xL, FLIP and Mcl-1 (P<0.005-0.01) in T cells. In addition, IRX-2 reversed MV-induced inhibition of the PI3K/Akt pathway. An Akt inhibitor (Akti-1/2) abrogated protective effects of IRX-2, suggesting that Akt is a downstream target of IRX-2 signaling. Thus, ex vivo pretreatment of CD8(+) T cells with IRX-2 provided potent protection from tumor-induced apoptosis. IRX-2 application to future cancer biotherapies could improve their effectiveness by bolstering T-cell resistance to tumor-induced immunosuppression.

| S-EPMC3721331 | biostudies-literature

Inhibition of diacylglycerol kinase ? restores restimulation-induced cell death and reduces immunopathology in XLP-1.

Project description:X-linked lymphoproliferative disease (XLP-1) is an often-fatal primary immunodeficiency associated with the exuberant expansion of activated CD8(+) T cells after Epstein-Barr virus (EBV) infection. XLP-1 is caused by defects in signaling lymphocytic activation molecule (SLAM)-associated protein (SAP), an adaptor protein that modulates T cell receptor (TCR)-induced signaling. SAP-deficient T cells exhibit impaired TCR restimulation-induced cell death (RICD) and diminished TCR-induced inhibition of diacylglycerol kinase ? (DGK?), leading to increased diacylglycerol metabolism and decreased signaling through Ras and PKC? (protein kinase C?). We show that down-regulation of DGK? activity in SAP-deficient T cells restores diacylglycerol signaling at the immune synapse and rescues RICD via induction of the proapoptotic proteins NUR77 and NOR1. Pharmacological inhibition of DGK? prevents the excessive CD8(+) T cell expansion and interferon-? production that occur in SAP-deficient mice after lymphocytic choriomeningitis virus infection without impairing lytic activity. Collectively, these data highlight DGK? as a viable therapeutic target to reverse the life-threatening EBV-associated immunopathology that occurs in XLP-1 patients.

| S-EPMC4918505 | biostudies-literature

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