TY - JOUR TI - Signal transducer and activator of transcription 5 (STAT5) paralog dose governs T cell effector and regulatory functions AU - Villarino, Alejandro AU - Laurence, Arian AU - Robinson, Gertraud W AU - Bonelli, Michael AU - Dema, Barbara AU - Afzali, Behdad AU - Shih, Han-Yu AU - Sun, Hong-Wei AU - Brooks, Stephen R AU - Hennighausen, Lothar AU - Kanno, Yuka AU - O'Shea, John J A2 - Glass, Christopher K VL - 5 PY - 2016 DA - 2016/03/19 SP - e08384 C1 - eLife 2016;5:e08384 DO - 10.7554/eLife.08384 UR - https://doi.org/10.7554/eLife.08384 AB - 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. KW - T cells KW - autoimmunity KW - STAT5 KW - cytokine KW - STAT signaling KW - transcription factors JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -