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

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.