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Asymmetry and redundancy of STAT5 paralogs across CD8+ T cell differentiation states

ABSTRACT: Fostering STAT5 signaling is key to immunotherapies that leverage CD8+ T cell biology. Using mouse models, we demonstrate that the two mammalian STAT5 paralogs, STAT5A and STAT5B, are at once redundant and functionally distinct in CD8+ T cells. Thus, they are asymmetric paralogs, exhibiting both widespread homology at molecular level and functional asymmetry at cellular level, with STAT5B emerging as dominant. For mechanisms, we determined that STAT5B is twice as abundant, accounting for two-thirds of the total STAT5 pool, and present evidence that it also has distinct, paralog-specific properties. We also defined cytokine- and cell state-restricted STAT5B functions and devised a core signature that spotlights key downstream properties and serves as bioinformatic probe. Together, these studies affirm the centrality of STAT5 in CD8+ T cells, reveal common and circumscribed activities for STAT5A and STAT5B, and present a unifying model that foregrounds both redundancy and asymmetry.

ORGANISM(S): Mus musculus

PROVIDER: GSE319829 | GEO | 2026/02/18

REPOSITORIES: GEO

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Essential role of STAT5 tyrosine phosphorylation in vivo

Project description:STAT5 proteins are vital for lymphocyte development and function. Tyrosine phosphorylation of a C-terminal tyrosine is the key event in cytokine activation of STAT5A and STAT5B. However, the role of STAT5 tyrosine phosphorylation has not been assessed in vivo. Here we generated Stat5a and Stat5b tyrosine mutant knock-in (KI) mice and found that these animals had greatly reduced CD8+ T cell numbers. These cells exhibited profoundly diminished proliferation in response to IL-2, correlating with greatly reduced IL-2-induced pRB and a block in the G1-->S phase transition. The mutant cells also exhibited decreased IL-2-mediated activation of pERK and pAKT, which can in part be attributed to diminished IL-2-induced expression of IL-2R-beta and IL-2R-gamma. Our findings highlight that the tyrosine phosphorylation of both STAT5A and STAT5B is essential for maximal IL-2 signaling and elucidate the molecular basis for achieving an optimal mitogenic effect of IL-2 on CD8+ T cells.

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Essential role of STAT5 tyrosine phosphorylation in vivo

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Critical Role of STAT5 Transcription Factor Tetramerization for Cytokine Responses and Normal Immune Function (ChIP-Seq and RNA-Seq)

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Project description:The transcription factor STAT5 is fundamental to the mammalian immune system. However, the relationship between its two paralogs, STAT5A and STAT5B, and the extent to which they are functionally distinct, remains controversial. We addressed this longstanding question in primary CD4+ 'helper' T cells, the principal orchestrators of adaptive immunity. Using a combination of genetic and genomic approaches, we demonstrate that, although both influence regulatory (Treg) and effector T cell responses, and control many of the same genes, they are not functionally equivalent and, in fact, only the latter is required for immunological tolerance. Differences in genomic distribution and transcriptomic output support the conclusion that STAT5B is dominant and, surprisingly, point towards relative abundance (i.e. paralog dose), rather than unique functional capabilities, as the principal distinguishing feature. Collectively, our data provide a unifying model for the discrete and redundant activities of STAT5A and STAT5B, establishing that asymmetrical expression underlies paralog specificity (or dominance) in the face of widespread structural homology. This dataset includes 55 individual samples of transcriptome or STAT5 distibution data from cytokine treated CD4+T cells. Each culture condition includes at least 2 biological replicates per genotype.

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Genetic modification of STAT5 levels reveals dose-dependent and isoform-specific requirement for cell lineage progression and differentiation.

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