Tonic TCR and IL-1β signaling mediate phenotypic alterations of naive CD4⁺ T cells

Inert naive CD4⁺ T (T_N) cells differentiate into functional T helper (Th) or regulatory T (Treg) cell subsets upon encountering antigens, mediating properly directed immune responses. Although all T_N cells can differentiate into any of the Th and Treg cell subsets, heterogeneity exists among T_N cells. By constructing reporter mice to detect ongoing T cell receptor (TCR) signaling, we identify that interleukin (IL)-1β signaling affects T_N cell characteristics, independent of tonic TCR signaling, which also alters T_N cell phenotypes. IL-1β reversibly attenuates the differentiation potential of T_N cells toward Treg cells. IL-1β signaling is elevated in the splenic T_N cells, consequently attenuating their differentiation potential toward Treg cells. Aberrant elevation of IL-1β signaling augments colitogenic activities of T_N cells. T_N cells in patients with colitis exhibited elevated IL-1β signaling. We demonstrate that phenotypic alteration in T_N cells by IL-1β is an important mechanism in the regulation of immune responses.