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Project description:T cell dysfunctionality prevents clearance of chronic infections and cancer. Furthermore, epigenetic programming in dysfunctional CD8+ T cells limits durable responses to T cell-based immunotherapies, including immune checkpoint blockade (ICB). However, major gaps concern how upstream signals drive acquisition of dysfunctional epigenetic programs, and whether therapeutically targeting these signals can remodel terminally dysfunctional T cells to an ICB-responsive state. Here, we use an in vitro model of human T cell dysfunction and complementary in vivo mouse chronic virus infection and tumor models. We show that post-effector TGFβ1 signaling establishes terminal dysfunction in human CD8+ T cells through stable epigenetic changes. Importantly, we demonstrate that promoting BMP signaling while blocking TGFβ1 restored effector and memory programs in dysfunctional human CD8+ T cells, induced superior anti-tumor activity, and boosted ICB responses during mouse chronic virus infection. Thus, rebalancing TGFβ1/BMP-signals in dysfunctional CD8+ T cells provides an exciting new approach to enhance T cell immunotherapies.
2022-11-03 | GSE217087 | GEO
Project description:T cell dysfunctionality prevents clearance of chronic infections and cancer. Furthermore, epigenetic programming in dysfunctional CD8+ T cells limits durable responses to T cell-based immunotherapies, including immune checkpoint blockade (ICB). However, major gaps concern how upstream signals drive acquisition of dysfunctional epigenetic programs, and whether therapeutically targeting these signals can remodel terminally dysfunctional T cells to an ICB-responsive state. Here, we use an in vitro model of human T cell dysfunction and complementary in vivo mouse chronic virus infection and tumor models. We show that post-effector TGFβ1 signaling establishes terminal dysfunction in human CD8+ T cells through stable epigenetic changes. Importantly, we demonstrate that promoting BMP signaling while blocking TGFβ1 restored effector and memory programs in dysfunctional human CD8+ T cells, induced superior anti-tumor activity, and boosted ICB responses during mouse chronic virus infection. Thus, rebalancing TGFβ1/BMP-signals in dysfunctional CD8+ T cells provides an exciting new approach to enhance T cell immunotherapies.
2022-11-03 | GSE217072 | GEO
Project description:Rebalancing TGFβ1/BMP Signals Preserves Effector and Memory Programs in Terminally Dysfunctional CD8+ T Cells
| PRJNA896918 | ENA
Project description:Rebalancing TGFβ1/BMP Signals Preserves Effector and Memory Programs in Terminally Dysfunctional CD8+ T Cells [RNA-Seq]
| PRJNA896866 | ENA
Project description:Rebalancing TGFβ1/BMP Signals Preserves Effector and Memory Programs in Terminally Dysfunctional CD8+ T Cells [Bisulfite-Seq]
| PRJNA896920 | ENA
Project description:We show the presence of lymphoid tissue-resident PLZF+ CD45RA+ RO+ CD4 T cells in humans. They express HLA-DR, granzyme B, and perforin and are low on CCR7 like terminally differentiated effector memory (Temra) cells and are likely generated from effector T cells (Te) or from central (Tcm) or effector (Tem) memory T (Tcm) cells during immune responses. Tn, Naïve T cells.
| S-EPMC6748641 | biostudies-literature
Project description:CD8(+) cytotoxic T lymphocytes play a major role in defense against intracellular pathogens, and their functions are specified by antigen recognition and innate cytokines. IL-12 and IFN-?/? are potent "signal 3" cytokines that are involved in both effector and memory cell development. Although the majority of effector cells are eliminated as inflammation resolves, some survive within the pool of memory cells and retain immediate effector function. In this study, we demonstrate that IL-12 instructs a unique program of effector cell differentiation that is distinct from IFN-?/?. Moreover, effector memory (T(EM)) cells within peripheral blood display many common attributes of cells differentiated in vitro in response to IL-12, including proinflammatory cytokine secretion and lytic activity. A pattern of IL-12-induced genes was identified that demarcate T(EM) from central memory cells, and the ontologies of these genes correlated precisely with their effector functions. Further, we uncovered a unique program of gene expression that was acutely regulated by IL-12 and reflected in stable gene expression patterns within T(EM), but not T central memory cells in vivo. Thus, this study directly links a selective set of IL-12-induced genes to the programming of effector functions within the stable population of human CD8(+) T(EM) cells in vivo.
| S-EPMC3193266 | biostudies-literature
Project description:BackgroundIdentifying biomarkers to predict kidney transplant failure and to define new therapeutic targets requires more comprehensive understanding of the immune response to chronic allogeneic stimulation.MethodsWe investigated the frequency and function of CD8+ T cell subsets-including effector memory (EM) and terminally differentiated EM (TEMRA) CD8+ T cells-in blood samples from 284 kidney transplant recipients recruited 1 year post-transplant and followed for a median of 8.3 years. We also analyzed CD8+ T cell reactivity to donor-specific PBMCs in 24 patients who had received living-donor kidney transplants.ResultsIncreased frequency of circulating TEMRA CD8+ T cells at 1 year post-transplant associated with increased risk of graft failure during follow-up. This association remained after adjustment for a previously reported composite of eight clinical variables, the Kidney Transplant Failure Score. In contrast, increased frequency of EM CD8+ T cells associated with reduced risk of graft failure. A distinct TEMRA CD8+ T cell subpopulation was identified that was characterized by expression of FcγRIIIA (CD16) and by high levels of proinflammatory cytokine secretion and cytotoxic activity. Although donor-specific stimulation induced a similar rapid, early response in EM and TEMRA CD8+ T cells, CD16 engagement resulted in selective activation of TEMRA CD8+ T cells, which mediated antibody-dependent cytotoxicity.ConclusionsAt 1 year post-transplant, the composition of memory CD8+ T cell subsets in blood improved prediction of 8-year kidney transplant failure compared with a clinical-variables score alone. A subpopulation of TEMRA CD8+ T cells displays a novel dual mechanism of activation mediated by engagement of the T-cell receptor or of CD16. These findings suggest that TEMRA CD8+ T cells play a pivotal role in humoral and cellular rejection and reveal the potential value of memory CD8+ T cell monitoring for predicting risk of kidney transplant failure.
| S-EPMC7191929 | biostudies-literature
Project description:γδ T-cells perform a wide range of tissue- and disease-specific functions that are dependent on the effector cytokines produced by these cells. However, the aggregate signals required for the development of interferon-γ (IFNγ) and interleukin-17 (IL-17) producing γδ T-cells remain unknown. Here, we define the cues involved in the functional programming of γδ T-cells, by examining the roles of T-cell receptor (TCR), Notch, and cytokine-receptor signaling. KN6 γδTCR-transduced Rag2-/- T-cell progenitors were cultured on stromal cells variably expressing TCR and Notch ligands, supplemented with different cytokines. We found that distinct combinations of these signals are required to program IFNγ versus IL-17 producing γδ T-cell subsets, with Notch and weak TCR ligands optimally enabling development of γδ17 cells in the presence of IL-1β, IL-21 and IL-23. Notably, these cytokines were also shown to be required for the intrathymic development of γδ17 cells. Together, this work provides a framework of how signals downstream of TCR, Notch and cytokine receptors integrate to program the effector function of IFNγ and IL-17 producing γδ T-cell subsets.
| S-EPMC6197911 | biostudies-literature
Project description:The T cell Ig- and mucin domain-containing molecule-3 (Tim-3) negative immune checkpoint receptor demarcates functionally exhausted CD8(+) T cells arising from chronic stimulation in viral infections like HIV. Tim-3 blockade leads to improved antiviral CD8(+) T cell responses in vitro and, therefore, represents a novel intervention strategy to restore T cell function in vivo and protect from disease progression. However, the Tim-3 pathway in the physiologically relevant rhesus macaque SIV model of AIDS remains uncharacterized. We report that Tim-3(+)CD8(+) T cell frequencies are significantly increased in lymph nodes, but not in peripheral blood, in SIV-infected animals. Tim-3(+)PD-1(+)CD8(+) T cells are similarly increased during SIV infection and positively correlate with SIV plasma viremia. Tim-3 expression was found primarily on effector memory CD8(+) T cells in all tissues examined. Tim-3(+)CD8(+) T cells have lower Ki-67 content and minimal cytokine responses to SIV compared with Tim-3(-)CD8(+) T cells. During acute-phase SIV replication, Tim-3 expression peaked on SIV-specific CD8(+) T cells by 2 wk postinfection and then rapidly diminished, irrespective of mutational escape of cognate Ag, suggesting non-TCR-driven mechanisms for Tim-3 expression. Thus, rhesus Tim-3 in SIV infection partially mimics human Tim-3 in HIV infection and may serve as a novel model for targeted studies focused on rejuvenating HIV-specific CD8(+) T cell responses.
| S-EPMC4239185 | biostudies-literature