FIGURE 2. The double selection model for Treg differentiation.

Starting at the CD4, 8 double negative stage 3 (DN3), thymocytes show low Foxp3 gene transcription (blue bars). Positive selection of common precursors of conventional (conT) and Treg cells occurs at the double positive stage (DP). Further selection processes involve negative selection of conT cells (A) by deletion of clones with high affinity TCR for self pMHCII on APCs in the cortical medullary junction (CMJ), leaving the majority of clones with medium affinity (thick arrow) to mature into functional Foxp3 negative, CD4⁺ helper T cells. Treg lineage differentiation (B) includes a second selection step (Treg positive) in which few CD4⁺Foxp3^lo thymocytes (thin arrow) engage in high affinity interactions with overly expressed medullary pMHCII to secure Foxp3 high expression in Treg permissive micro environments (IL-7 and TSLP).