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TNFR2 loss prevents TOX upregulation in CD8+TIM3+ T cells and affords improved responses to tumor and chronic LCMV

ABSTRACT: Preview PDF Abstract Exhaustion represents a collection of programmed T cell differentiation states and an important mode of T cell dysfunction. T cell progression from progenitor to terminal exhaustion is associated with upregulation of the transcription factor TOX and expression of TIM3. Our understanding of factors regulating TOX expression and the transition from progenitor to terminal exhaustion, however, remains incomplete. We reveal here that T cell upregulation of tumor necrosis factor receptor type II (TNFR2) coincides with the gain of phenotypic markers and functions reflective of terminal exhaustion. Meanwhile, knocking out TNFR2 affords a novel population of T cells that express TIM3 but possess diminished TOX levels and functional characteristics of both progenitor and terminally exhausted cells. TIM3+ TNFR2 KO T cells exhibit reduced exhaustion transcriptional programs and enhanced AP1 pathway signatures. Finally, TNFR2 KO mice demonstrate improved T cell-dependent control of tumor and chronic lymphocytic choriomeningitis viral (cLCMV) infection, while pharmacologic antagonism of TNFR2 licenses responses to checkpoint blockade in multiple tumor models.

ORGANISM(S): Mus musculus

PROVIDER: GSE297330 | GEO | 2025/05/19

REPOSITORIES: GEO

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TNFR2 loss prevents TOX upregulation in CD8+TIM3+ T cells and affords improved responses to tumor and chronic LCMV

Project description:TNFR2 loss prevents TOX upregulation in CD8+TIM3+ T cells and affords improved responses to tumor and chronic LCMV

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Tumor-activating IL2 rejuvenates intratumoral TIM3-CD8+T cell responses through targeting TIM3+CD8+T cell

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2025-05-22 | GSE296919 | GEO

Altered costimulatory signaling and hypoxia support chromatin landscapes that limit the functional potential of exhausted T cells in cancer [CUT&RUN]

Project description:Increases in terminally exhausted T cells in the tumor are associated with poor responses to immunotherapy, yet the mechanisms that promote progression to terminal exhaustion remain undefined. We profiled the chromatin landscape of subsets of tumor-infiltrating CD8+ T cells using CUT&RUN. CD8 T cells were sorted from the murine B16 melanoma tumor using PD1 and Tim3 expression to define four subsets: PD1lo, PD1mid, PD1hi, and PD1hiTim3+. Additional control samples include paired CD44+ cells from the tumor-draining lymph node of tumor bearing mice, and OT-I effector CD8 T cells isolated from Vaccinia-ova infection. We performed CUT&RUN for H3K4me3, H3K27me3, H3K27ac, and H3K9ac, as well as the transcription factors Tox and Batf.

2022-08-04 | GSE175437 | GEO

Tox reinforces the phenotype and longevity of dysfunctional T cell populations during chronic viral infection [WT vs KO +/- Tim3]

Project description:Chronic CD8 T-cell stimulation in persisting infections or tumors can induce a stable gene expression program, known as T-cell dysfunction or exhaustion, that limits the cell’s effector functions and anti-viral and anti-tumor immunity. Thus far, the underlaying molecular mechanisms that induce and stabilize this phenotype are vaguely understood. We report here that establishing this program requires the thymocyte selection-associated high mobility group-box protein (Tox). Genetic disruption of Tox augments effector function, decreases the expression of PD-1, and significantly enhances immunopathology. These changes are linked to a failure in fixing the dysfunctional phenotype in the critical Tcf1+ progenitor population and to impaired epigenetic programing. Surprisingly, the gains in effector function co-incide with declining numbers of Tcf1+ cells and result ultimately in reduced total numbers of pathogen-specific T-cells. Thus, we establish Tox as a critical factor for the development of T-cell dysfunction and establish a clear link between CD8 T-cell intrinsic suppression of effector function and protection against immune-pathology.

2019-07-03 | GSE132033 | GEO

Identification of a T-bet hi Quiescent Exhausted CD8 T Cell Subpopulation That Can Differentiate into TIM3 + CX3CR1 + Effectors and Memory-like Cells

Project description:Persistent Ag induces a dysfunctional CD8 T cell state known as "exhaustion" characterized by PD-1 expression. Nevertheless, exhausted CD8 T cells retain functionality through continued differentiation of progenitor into effector cells. However, it remains ill-defined how CD8 T cell effector responses are sustained in situ. In this study, we show using the mouse chronic lymphocytic choriomeningitis virus infection model that CX3CR1+ CD8 T cells contain a T-bet-dependent TIM3-PD-1lo subpopulation that is distinct from the TIM3+CX3CR1+PD-1+ proliferative effector subset. The TIM3-CX3CR1+ cells are quiescent and express a low but significant level of the transcription factor TCF-1, demonstrating similarity to TCF-1hi progenitor CD8 T cells. Furthermore, following the resolution of lymphocytic choriomeningitis virus viremia, a substantial proportion of TCF-1+ memory-like CD8 T cells show evidence of CX3CR1 expression during the chronic phase of the infection. Our results suggest a subset of the CX3CR1+ exhausted population demonstrates progenitor-like features that support the generation of the CX3CR1+ effector pool from the TCF-1hi progenitors and contribute to the memory-like pool following the resolution of viremia.

2021-04-13 | GSE148497 | GEO

Tumor-activating IL2 rejuvenates intratumoral TIM3-CD8+T cell responses through targeting TIM3+CD8+T cell

Project description:Tumor-activating IL2 rejuvenates intratumoral TIM3-CD8+T cell responses through targeting TIM3+CD8+T cell

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The TET2 methylcytosine dioxygenase regulates early and late transitions in exhausted CD8+ T-cell differentiation

Project description:Epigenetic reprogramming of CAR T-cells by targeting TET2, a methylcytosine deoxygenase that mediates active DNA demethylation, has shown therapeutic potential; however, the role of TET2 in TEX development is unclear. In both CAR T-cell exhaustion models in vitro and chronic LCMV infection in vivo, TET2 drove the conversion from memory-like, self-renewing TEX progenitors towards effector (TEFF)-like and terminally differentiated TEX. TET2-deficient terminally differentiated TEX retained aspects of TEX progenitor biology, including decreased expression of the transcription factor TOX, suggesting that TET2 is required for terminal exhaustion.

2025-04-14 | GSE261093 | GEO

Tox reinforces the phenotype and longevity of dysfunctional T cell populations during chronic viral infection [WT vs KO +/- Tim3]

Project description:Tox reinforces the phenotype and longevity of dysfunctional T cell populations during chronic viral infection [WT vs KO +/- Tim3]

| PRJNA545703 | ENA

Altered costimulatory signaling and hypoxia support chromatin landscapes that limit the functional potential of exhausted T cells in cancer [RNA-seq]

Project description:Increases in terminally exhausted T cells in the tumor are associated with poor responses to immunotherapy, yet the mechanisms that promote progression to terminal exhaustion remain undefined. To understand the effect of epigenetic changes in subsets of tumor-infiltrating CD8+ T cells, we performed RNA-seq to understand changes in gene expression. CD8 T cells were sorted from the murine B16 melanoma tumor using PD1 and Tim3 expression to define four subsets: PD1lo, PD1mid, PD1hi, and PD1hiTim3+. Additional control samples include paired CD44+ cells from the tumor-draining lymph node of tumor bearing mice, and OT-I effector CD8 T cells isolated from Vaccinia-ova infection. CD8 TIL PD1hi Tim3+ from B16 tumors treated with IgG control, anti-PD1 or anti-41BB agonist immunotherapies were also isolated for RNAseq.

2022-08-04 | GSE175408 | GEO

Transcriptome differences in HCC infiltrated CD8+ T cells in effector and exhaustion state

Project description:CD8+ T cells isolated from HCC tissue were divided into three groups: PD1-TIM3- CD8+ TILs, exhibiting full effector function; PD1-intTIM3+ CD8+ TILs, exhibiting partial exhaustion; and PD1-hiTIM3+ CD8+ TILs, exhibiting severe exhaustion, as reflected by the differences in their ability to produce effector cytokines respectively. Transcriptome sequence analysis was performed to investigate the gene expression profile was performed.

2019-12-31 | E-MTAB-7278 | biostudies-arrayexpress

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