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

Abstract

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.

The Role of Regulatory T Cells in Allergic Diseases: Collegium Internationale Allergologicum (CIA) Update 2024

“…The persistence of late agonist signaling in the CD25 + precursors contributes to the generation of effector CD4 + T cells, whereas disruption of late agonist signaling by transforming growth factor (TGF)-β promotes the generation of mature tTregs (Fig. 1) [19,20]. This Treg subset is predominant in bloodstream and in lymph nodes.…”

Deciphering the factors determining the differentiation of autoreactive thymocytes into regulatory T cells

“…In conclusion, the factors that determined whether an immature T cell that recognize self-antigens with high avidity was deleted or differentiated into Treg and the specific implication of TGFβ were not clear. 7,8 Tai et al 4…”

Deconstructing Complexity: A Computational Topology Approach to Trajectory Inference in the Human Thymus withtviblindi

“…During these processes the cells acquire the chemokine receptor CCR7 and move from the thymic cortex to the medulla, where tissue-specific self-antigens are ectopically expressed on the surface of medullary epithelial cells (22,23) . The current models suggest that both the strength/duration of TCR signal (24–27) and the integration of TCR signals from consecutive T cell – antigen-presenting cell encounters (28,29) help to determine the autoreactive T-cell fate. Costimulatory signals (30–32) as well as cytokines (33–39) contribute to the process.…”