Ristin Svetlana, Dalzell Molly, Armstrong Christopher, Ilsin Nisa, Fontanella Antonio M, Nivelo Luis, Hennighausen Lothar, O'Shea John J, Villarino Alejandro V
Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA.
Sylvester Comprehensive Cancer Center, University of Miami, Miami, USA.
bioRxiv. 2025 Jul 28:2025.07.23.666302. doi: 10.1101/2025.07.23.666302.
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. Specifically, we establish that they are , exhibiting both widespread homology at molecular level and functional asymmetry at cellular level, with STAT5B emerging as dominant. In fact, compared to STAT5A, STAT5B deficiency had greater impact on nearly all parameters tested. As a mechanism, we determined STAT5B is twice as abundant, accounting for two-thirds of the total STAT5 pool. We also defined both cytokine- and cell state-restricted STAT5B functions, and a core gene signature that highlights universal effects. Together, these studies affirm the centrality of STAT5 in CD8 T cells, reveal common and circumscribed activities, and present a unifying model for paralog redundancy that foregrounds and explains the dominance of STAT5B.
促进信号转导及转录激活因子5（STAT5）信号传导是利用CD8 T细胞生物学特性的免疫疗法的关键。通过小鼠模型，我们证明了两种哺乳动物STAT5旁系同源物，即STAT5A和STAT5B，在CD8 T细胞中既具有冗余性又在功能上有所不同。具体而言，我们证实它们在分子水平上表现出广泛的同源性，在细胞水平上具有功能不对称性，其中STAT5B占主导地位。事实上，与STAT5A相比，STAT5B缺陷对几乎所有测试参数的影响更大。作为一种机制，我们确定STAT5B的丰度是STAT5A的两倍，占STAT5总量的三分之二。我们还定义了细胞因子和细胞状态限制的STAT5B功能，以及一个突出普遍效应的核心基因特征。总之，这些研究证实了STAT5在CD8 T细胞中的核心地位，揭示了其共同和特定的活性，并提出了一个旁系同源物冗余的统一模型，该模型突出并解释了STAT5B的主导地位。
