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

This study investigates how autoreactive thymocytes, bearing T cell receptors (TCRs) with high affinity for self-ligands, differentiate into regulatory T (Treg) or effector T (Teff) CD4+ cells after escaping clonal deletion. The researchers found that deletion and differentiation are time-dependent agonist-signaled events. Treg and Teff cells arise from agonist-signaled CD4+CD25+ precursors, with TGF-β playing a crucial role in directing lineage fate by disrupting weaker agonist signals to promote Treg development. Conversely, persistent agonist signaling drives Teff cell differentiation. IL-2 only initiates Foxp3 expression under non-physiological conditions. The study concludes that TCR signaling disruption versus persistence is a key mechanism determining lineage fate during thymic selection of 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