IL-27 and TCR stimulation promote T cell expression of multiple inhibitory receptors
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PROVIDER: PRJNA511005 | ENA |
REPOSITORIES: ENA
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Project description:Inhibitory receptors (IR) are a diverse group of cell surface molecules that modulate T cell activation, but there are gaps in our knowledge of the cell extrinsic factors that regulate their expression. The present study found that in vivo overexpression of IL-27 led to increased T cell expression of PD-L1, LAG-3, TIGIT, and TIM-3. In vitro, TCR stimulation alone promoted expression of multiple IRs, while IL-27 alone induced expression of PD-L1. However, the combination of intermediate TCR stimulation and IL-27 resulted in synergistic induction of LAG-3, CTLA-4, and TIGIT. In vivo, infection with Toxoplasma gondii resulted in parasitespecific effector T cells that expressed high levels of IR and at local sites of infection where IL-27 production was highest, IL-27 was required for maximal effector cell expression of PD-L1, LAG-3, CTLA-4 and TIGIT. Together, these results affirm the critical role of TCR signals in the induction of IR expression, but find that during infection, IL-27 provides a signal that promotes T cell expression of inhibitory receptors.
2019-01-17 | GSE124222 | GEO
Project description: Not available
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Project description:CD8+ T cells responding to chronic viral infection adapt to continuous antigenic stimulation by the upregulation of inhibitory receptors. Here we addressed how memory-like CD8+ T cells (TML), which sustain the immune response in chronic infection due to their stem cell-like properties, adapt to chronic stimulation when they cannot express the co-inhibitory receptor PD-1. We found that PD-1 deficient TML cells did not show evidence of a compensatory increases in the expression of other inhibitory receptors or exhaustion-related genes. Rather, these cells displayed a reduced ability to activate multiple signaling pathways downstream of the TCR. By-passing proximal TCR signaling events restored the activation of PD-1-deficient TML cells. Consistent with reduced TCR signaling, PD-1-deficient TML cells had a reduced ability to expand and self-renew in response to recall stimulation. Transient blockade of PD-1/PD-L1 interaction similarly reduced the stemness of TML cells. Thus, in the absence of PD-1, stem-like CD8+ T cells adapt to chronic stimulation by reducing the capacity of the TCR to transmit activating signals, which limits the stemness of these cells. Thus, PD-1 preserves the stemness of TML cells ensuring the long-term maintenance of the immune response to chronic infection.
2026-01-16 | GSE277649 | GEO
Project description:CD8+ T cells responding to chronic viral infection adapt to continuous antigenic stimulation by the upregulation of inhibitory receptors. Here we addressed how memory-like CD8+ T cells (TML), which sustain the immune response in chronic infection due to their stem cell-like properties, adapt to chronic stimulation when they cannot express the co-inhibitory receptor PD-1. We found that PD-1 deficient TML cells did not show evidence of a compensatory increases in the expression of other inhibitory receptors or exhaustion-related genes. Rather, these cells displayed a reduced ability to activate multiple signaling pathways downstream of the TCR. By-passing proximal TCR signaling events restored the activation of PD-1-deficient TML cells. Consistent with reduced TCR signaling, PD-1-deficient TML cells had a reduced ability to expand and self-renew in response to recall stimulation. Transient blockade of PD-1/PD-L1 interaction similarly reduced the stemness of TML cells. Thus, in the absence of PD-1, stem-like CD8+ T cells adapt to chronic stimulation by reducing the capacity of the TCR to transmit activating signals, which limits the stemness of these cells. Thus, PD-1 preserves the stemness of TML cells ensuring the long-term maintenance of the immune response to chronic infection.
2026-01-16 | GSE277648 | GEO
Project description:Viral vectors are attractive vaccine platforms that elicit robust innate and adaptive immune responses; however, viral vector vaccine candidates vary greatly in their ability to induce protective immunity. Ad5 vectors elicit robust CD8+ T cell responses but typically characterized by an exhausted phenotype. The mechanisms by which Ad5 vectors induce dysfunctional CD8+ T cells have not been fully elucidated. Here we demonstrate that Ad5 vectors, but not Ad26 vectors, elicit exhausted antigen-specific IL-10+PD1+ CD4+ T cells with a dysfunctional transcriptional profile, and these cells effectively suppress CD8+ T cells responses in vivo. Induction of inhibitory CD4+ T cells by Ad5 vectors was associated with increased IL-27 expression, and IL-27 blockade improved CD4+ T cell polyfunctionality. Together our data highlight a novel role for IL-27 in regulating responses to viral vector vaccines. Splenic CD45.2+ OT-II TCR-Tg CD4 T cells from CD45.1+ B6 mice immunized with Ad5-OVA or Ad26-OVA were purified by FACS on day 10 post-immunization
2016-06-01 | E-GEOD-73118 | biostudies-arrayexpress
Project description:Chimeric antigen receptor (CAR)-expressing T-cells induce durable remissions in patients with relapsed/refractory B-cell malignancies. CARs are artificial constructs introduced into mature T-cells conferring a second, non-MHC restricted specificity in addition to the endogenous T-cell receptor (TCR). The impact of TCR activation on CAR T-cell efficacy in vivo has important implications for clinical optimization of CAR T-cell therapy, but cannot be systematically evaluated in xenograft models. Using an immunocompetent, syngeneic murine model of CD19-targeted CAR T-cell therapy for pre-B cell ALL, we demonstrate loss of CD8 CAR T-cell mediated clearance of leukemia associated with T-cell exhaustion and apoptosis when TCR antigen is present. CD4 CAR T-cells demonstrate equivalent cytotoxicity, as compared to CD8 CAR T-cells, and in contrast, retain in vivo efficacy in the presence of TCR stimulation. Gene expression profiles confirm increased exhaustion and apoptosis of CAR8 upon dual receptor stimulation compared to CAR4, and indicate inherent differences in T-cell pathways. Chimeric antigen receptor (CAR) T cells express two activating receptors, the CAR and the endogenous T cell receptor (TCR). CAR T cells can be derived from either CD8 or CD4 T cells to generate CAR8 and CAR4 cells, respectively. In vivo, CAR8 and CAR4 cells respond differently when simultaneously stimulated through the CAR and TCR.
2017-12-31 | GSE103632 | GEO
Project description:Chimeric antigen receptor T (CAR-T) cell therapies for B cell malignancies demonstrate high response rate and durable disease control. However, in the case of solid tumors, CAR-T cells have shown dysfunction ascribed to some intrinsic defects in CAR signaling. Here, we construct a multi-chain chimeric receptor, termed as Synthetic T Cell Receptor and Antigen Receptor (STAR), which incorporates antigen-recognition domain of antibody and engages entire CD3 signaling machinery of T cell receptor (TCR). In multiple solid tumor models, STAR-T cells prominently outperform CAR-T cells without notable toxicity. STAR triggers strong and sensitive TCR-like signaling upon antigen stimulation. We compared the transcriptional profiles of STAR/CAR/TCR-T cells after stimulation for different time points (0, 6, 24, 72 hours), in order to figure out whether signaling difference of these receptors led to distinct gene expression. Our results showd that STAR activation phencopied TCR, while CAR drove a different program, displayed as various pathways related to effector function, cytokine response and cell survival were altered.
2021-02-14 | GSE160311 | GEO
Project description:Human Colonic CD4 T cells consist of several subsets differing in their expression of CD161. We exposed these cells to either cytokine, TCR or combined stimulation and assessed the subsequent changes in gene and protein expression with an emphasis on cytokine receptors and gene associated with tissue repair.
2022-07-02 | GSE207159 | GEO
Project description:Foxp3 expressing regulatory T cells (Tregs) are the central regulator of immune homeostasis and tolerance. As it is believed that proper Treg function is compromised under inflammatory conditions, exploring a pathway that enhances Treg function is of great importance. In this study, we report that IL-27, an IL-12 family cytokine known to play both pro- and anti-inflammatory role in T cells, plays a pivotal role in Treg function to control T cell-induced colitis. Unlike WT Tregs capable of inhibiting colitogenic T cell expansion and inflammatory cytokine expression, IL-27R-deficient Tregs were unable to downregulate inflammatory T cell responses. Tregs stimulated with IL-27 expressed substantially enhanced suppressive function both in vitro and in vivo. IL-27 stimulation of Tregs induced expression of LAG3, a surface molecule implicated in negatively regulating immune responses. LAG3 expression in IL-27-stimulated Tregs was critical to mediate suppressive Treg function. Finally, human Tregs also displayed enhanced suppressive function and LAG3 expression in response to IL-27 stimulation. Taken together, our results highlight a novel function of the IL-27/LAG3 axis in Treg regulation of inflammatory responses in the intestine.
2015-11-01 | GSE63455 | GEO
Project description:Viral vectors are attractive vaccine platforms that elicit robust innate and adaptive immune responses; however, viral vector vaccine candidates vary greatly in their ability to induce protective immunity. Ad5 vectors elicit robust CD8+ T cell responses but typically characterized by an exhausted phenotype. The mechanisms by which Ad5 vectors induce dysfunctional CD8+ T cells have not been fully elucidated. Here we demonstrate that Ad5 vectors, but not Ad26 vectors, elicit exhausted antigen-specific IL-10+PD1+ CD4+ T cells with a dysfunctional transcriptional profile, and these cells effectively suppress CD8+ T cells responses in vivo. Induction of inhibitory CD4+ T cells by Ad5 vectors was associated with increased IL-27 expression, and IL-27 blockade improved CD4+ T cell polyfunctionality. Together our data highlight a novel role for IL-27 in regulating responses to viral vector vaccines.
2016-06-01 | GSE73118 | GEO