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Themis directs T cell exhaustion by promoting PD-1 signaling and regulating expression of transcription factors TCF-1 and TOX

ABSTRACT: T cell exhaustion is a protective mechanism during chronic viral infections, but it can impair anti-tumor immunity. Themis, a T cell-specific protein, is critical for CD8+ T cell homeostasis, cytokine responsiveness, and anti-Listeria responses. In Themis-deficient mice infected with LCMV C13, a chronic virus, we observed severe lung injury and premature death. Single-cell analysis revealed that Themis-deficient effector CD8+ T cells, while producing higher levels of TNF and IFN-γ, were impaired in population expansion due to poor cell sustainability. Biochemical studies showed that Themis binds PD-1, promoting PD-1 phosphorylation and SHP-2 recruitment. Beyond its role in restraining effector T cell function, Themis is essential for the development of Tpex cells by promoting TCF-1 expression and driving transcriptional and epigenetic changes. Moreover, Themis supports TOX and PD-1 expression, ensuring the maintenance of terminally exhausted T cells (Tex). This study reveals the multifaceted roles of Themis in the progression of T cell exhaustion.

ORGANISM(S): Mus musculus

PROVIDER: GSE285487 | GEO | 2025/12/25

REPOSITORIES: GEO

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Gene expression profiles of Themis-deficient thymocytes

Project description:Determine the biochemical cause of impaired development of Themis-deficient thymocytes. We isolated three thymocyte populations (three populations: CD4+CD8+CD5loCD69lo, CD4+CD8+CD5+CD69+, and CD4+CD8-CD24hiH2Klo) from Themis-deficient and WT mice. 8 or 9 individual biological replicates were analyzed for each population. An aliquot of cDNA from each sample was pooled and used as a reference.

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Themis directs T cell exhaustion by promoting PD-1 signaling and key transcription factors TCF-1 and TOX expression

Project description:Themis directs T cell exhaustion by promoting PD-1 signaling and key transcription factors TCF-1 and TOX expression

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