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

Autor: Tai, Xuguang, Indart, Alyssa, Rojano, Mirelle, Guo, Jie, Apenes, Nicolai, Kadakia, Tejas, Craveiro, Marco, Alag, Amala, Etzensperger, Ruth, Badr, Mohamed Elsherif, Zhang, Flora, Zhang, Zhongmei, Mu, Jie, Guinter, Terry, Crossman, Assiatu, Granger, Larry, Sharrow, Susan, Zhou, Xuyu, Singer, Alfred
Zdroj: Nature Immunology; 20230101, Issue: Preprints p1-15, 15p
Abstrakt: 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 Tregand Teffcells 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 Tregcells, whereas persistent agonist signaling induces CD4+CD25+precursors to become IL-2+Teffcells. Notably, we discovered that transforming growth factor-β induces Foxp3 expression and promotes Tregcell 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.
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