Cytokine-independent activation of STAT5 promotes the persistence and function of CD4+ regulatory T cells.

Regulatory T cells (Tregs) prevent autoimmunity by suppressing self-reactive immune cells that can damage healthy tissues. Accordingly, therapeutics designed to promote Treg expansion and function, including IL-2 receptor (IL-2R) agonists and adoptive Treg therapies, have been used to treat autoimmune disease. However, the efficacy of these strategies has been hindered by the effects of IL-2 on activated immune cell populations, which can exacerbate inflammation, and by the limited persistence and functionality of Treg therapies. Because Tregs are dependent on IL-2R signaling that is mediated by STAT5, we evaluated a strategy to bypass IL-2R and activate STAT5 in a cytokine-independent manner in CD4+ T cells. We determined that an engineered variant of the herpesvirus saimiri tyrosine kinase interacting protein induced the phosphorylation of STAT5 in CD4+ T cells in the absence of IL-2 to promote their survival, as well as the differentiation and maintenance of Tregs ex vivo. This STAT5 activator (aSTAT5) enhanced Treg engraftment in mice and prevented the onset of colitis. Tregs that expressed aSTAT5 better maintained their lineage and were more effective at suppressing pathogenic inflammatory T cells. Our findings demonstrate a new approach to equip Tregs with the signals they need to maintain their suppressive capacity.