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Enhanced STAT5a activation opposes Tox and rewires exhausted CD8 T cells towards a hybrid durable effector-like state during chronic stimulation [CITE-seq_PostInfection]

ABSTRACT: Here, we discovered a reciprocal antagonism between Stat5a and Tox in TEX cells. Stat5a antagonized the Tox-mediated exhaustion program to achieve a durable and protective hybrid effector/NK-like differentiation state in settings that typically drive exhaustion. Stat5 also drove TEX progenitors to differentiate into the effector-like TEXint subset, a key developmental step for PD-1 blockade responsiveness.

ORGANISM(S): Mus musculus

PROVIDER: GSE214114 | GEO | 2023/05/31

REPOSITORIES: GEO

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Enhanced STAT5a activation opposes Tox and rewires exhausted CD8 T cells towards a hybrid durable effector-like state during chronic stimulation [scRNA-seq_PostInfection]

2023-05-31 | GSE214113 | GEO

Enhanced STAT5a activation opposes Tox and rewires exhausted CD8 T cells towards a hybrid durable effector-like state during chronic stimulation [ATAC-Seq]

Project description:Here, we discovered a reciprocal antagonism between Stat5a and Tox in TEX cells. Stat5a antagonized the Tox-mediated exhaustion program to achieve a durable and protective hybrid effector/NK-like differentiation state in settings that typically drive exhaustion. Stat5 also drove TEX progenitors to differentiate into the effector-like TEXint subset, a key developmental step for PD-1 blockade responsiveness. Therapeutic enhancement of Stat5 activity in TEX cells using an orthogonal IL-2/IL2Rb pair system fostered TEXint cell accumulation and synergized with PD-L1 blockade. Finally, targeted delivery of Stat5-signals in TEX progenitors achieved partial epigenetic rewiring of these cells towards the effector/memory lineage and revived polyfunctionality. Together, these data highlight therapeutic opportunities of targeting Stat5 to antagonize the Tox-dependent epigenetic programming of TEX and provoke a hybrid program that exploits effector biology and durability for optimal therapeutic potential

2023-08-31 | GSE240431 | GEO

Enhanced STAT5a activation opposes Tox and rewires exhausted CD8 T cells towards a hybrid durable effector-like state during chronic stimulation [ATAC-postInfection]

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Enhanced STAT5a activation opposes Tox and rewires exhausted CD8 T cells towards a hybrid durable effector-like state during chronic stimulation [ATAC-postChallenge]

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Stat5 antagonizes Tox and CD8 T cell exhaustion to foster a durable effector-like state during chronic antigen exposure

Project description:Constitutive Stat5a activity antagonized Tox and rewired CD8 T cells away from exhaustion to acquire a durable effector/NK-like state with superior anti-tumor potential Stat5 fostered TEXint, temporally re-engaging the Stat5 pathway, partially reprogrammed the epigenetic landscape of exhaustion and restored effector-like differentiation and function cell formation and partial re-acquisition of effector-biology during this TEXprog-to-TEXint transition,

2023-08-31 | GSE238239 | GEO

Innate lymphoid cell development requires TOX-dependent generation of a common ILC progenitor

Project description:Subtypes of innate lymphoid cells (ILC), defined by effector function and transcription factor expression, have recently been identified. In the adult, ILC derive from common lymphoid progenitors in bone marrow, although transcriptional regulation of the developmental pathways involved remains poorly defined. TOX is required for development of lymphoid tissue inducer cells, a type of ILC3 required for lymph node organogenesis, and NK cells, a type of ILC1. We show here that production of multiple ILC lineages requires TOX, as a result of TOX-dependent development of common ILC progenitors. Comparative transcriptome analysis demonstrated failure to induce various aspects of the ILC gene program in the absence of TOX, implicating this nuclear factor as a key early determinant of ILC lineage specification. TOX KO vs. wild tyype

2015-04-27 | E-GEOD-65850 | biostudies-arrayexpress

Tox reinforces the phenotype and longevity of exhausted T-cells in chronic viral infection [Bisulfite-Seq]

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 | GSE131642 | GEO

Tox reinforces the phenotype and longevity of exhausted T-cells in chronic viral infection [ATAC-seq]

2019-07-03 | GSE131638 | GEO

Oncogenic role of TOX in CTCL

Project description:TOX is a nuclear factor essential for the development of CD4+ T cells in the thymus. TOX is found to be aberrantly up-regulated in the skin biopsies and in the blood CD4+ T cells of cutaneous T cell lymphoma. The goal of this study is to identify potential transcriptional targets of TOX in CTCL by comparison between TOX shRNA transfected CTCL cells (Hut78 and HH) and control CTCL cells. Two color experiment. Lentivirus transduced control vector vs. TOX shRNA vectors on Hut78 and HH cell lines. Biological replicates: 3 control replicates, 3 shRNA tansduced replicates for each cell line.

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

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