Signal transducer and activator of transcription 5 (STAT5) paralog dose governs T cell effector and regulatory functions

作者：Alejandro V. Villarino, Arian Laurence, Gertraud W. Robinson, Michael Bonelli, Bárbara Dema, Behdad Afzali, Han‐Yu Shih, Hong‐Wei Sun, Stephen R. Brooks, Lothar Hennighausen, Yuka Kanno, John J. O’Shea · 发表于：eLife · 年份：2016 · DOI：10.7554/elife.08384 · 被引用次数：90 · 研究领域：T-cell and B-cell Immunology、Immune Cell Function and Interaction、Immune Response and Inflammation

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, remain uncertain. Using mouse models of paralog deficiency, we demonstrate that they are not equivalent for CD4(+) 'helper' T cells, the principal orchestrators of adaptive immunity. Instead, we find that STAT5B is dominant for both effector and regulatory (Treg) responses and, therefore, uniquely necessary for immunological tolerance. Comparative analysis of genomic distribution and transcriptomic output confirm that STAT5B has fargreater impact but, surprisingly, the data point towards asymmetric expression (i.e. paralog dose), rather than distinct functional properties, as the key distinguishing feature. Thus, we propose a quantitative model of STAT5 paralog activity whereby relative abundance imposes functional specificity (or dominance) in the face of widespread structural homology.