How autoreactive thymocytes differentiate into regulatory versus effector CD4⁺ T cells after avoiding clonal deletion

Thymocytes bearing autoreactive T cell receptors (TCRs) are agonist-signaled by TCR/co-stimulatory molecules to either undergo clonal deletion or to differentiate into specialized regulatory T (Treg) or effector T (Teff) CD4+ cells. How these different fates are achieved during development remains poorly understood. We now document that deletion and differentiation are agonist-signaled at different times during thymic selection and that Treg and Teff cells both arise after clonal deletion as alternative lineage fates of agonist-signaled CD4+CD25+ precursors. Disruption of agonist signaling induces CD4+CD25+ precursors to initiate Foxp3 expression and become Treg cells, whereas persistent agonist signaling induces CD4+CD25+ precursors to become IL-2 Teff cells. Notably, we discovered that transforming growth factor-β induces Foxp3 expression and promotes Treg cell development by disrupting weaker agonist signals and that Foxp3 expression is not induced by IL-2 except under non-physiological in vivo conditions. Thus, TCR signaling disruption versus persistence is a general mechanism of lineage fate determination in the thymus that directs development of agonist-signaled autoreactive thymocytes.

Xuguang Tai, Alyssa Indart, Mirelle Rojano, Jie Guo, Nicolai Apenes, Tejas Kadakia, Marco Craveiro, Amala Alag, Ruth Etzensperger, Mohamed Elsherif Badr, Flora Zhang, Zhongmei Zhang, Jie Mu, Terry Guinter, Assiatu Crossman, Larry Granger, Susan Sharrow, Xuyu Zhou, Alfred Singer