Description:
<jats:title>Abstract</jats:title><jats:p>OX40 stimulation is known to enhance activation of effector T cells and to inhibit induction and suppressive function of Treg. Here we uncovered a novel role of OX40 in sustaining Treg competitive fitness <jats:italic>in vivo</jats:italic>, during repopulation of lymphopenic hosts and reconstitution of BM chimeras. Defective expansion of OX40‐null Treg diminished their ability to suppress inflammation in a model of lymphopenia‐driven colitis. OX40‐mediated promotion of Treg fitness spanned beyond lymphopenic environments, as endogenous Treg in OX40‐null mice showed decreased accumulation during thymic development, enhanced susceptibility to antibody‐mediated depletion and defective turnover following thymectomy. <jats:italic>In vitro</jats:italic>, OX40‐deficient Treg were found to be intrinsically hyporesponsive to IL‐2, in terms of Stat5 phosphorylation and proliferation, according to elevated SOCS1 content and reduced miR155 expression. Therefore, OX40 is a key factor in shaping Treg sensitivity to IL‐2 and promoting their proliferation and survival, toward accurate immune regulation.</jats:p>