Figure 2.

Treg development in the thymus and periphery. (1) Naïve CD4⁺ T cells in the thymus test their T cell receptor (TCR) against the major histocompatibility complex (MHC); those with a low binding affinity that are CD25⁺ may circulate in the periphery; others lacking CD25 become helper T cells. Those cells with moderate affinity to self-antigens are selected to become natural Tregs (nTreg). Cells with strong binding to self-antigens undergo apoptosis [28]. (2a) Those cells with moderate binding are exposed to IL-2 secreted by thymic cells, which (3a) stimulates FOXP3 expression and differentiation into a mature natural Treg [22,29]. (2b,3b) In the periphery, circulating naïve cells may be exposed to TGF-β, which encourages differentiation into a mature induced Treg (iTreg) [26].