Fig. 3.

Transcriptional regulations of Treg homeostasis, tissue Treg precursors and tissue-specific Treg phenotype. Treg cells undergo a process of activation and differentiation in the SLOs. This is correlated with the upregulation (e.g., IRF4) and downregulation (e.g., TCF1, LEF1 and Id3) of different TFs. Recent studies have identified tissue Treg precursors in the SLOs, marked by either low level of PPARγ, the expression of Nfil3, or the “turning-off” of TCF1, LEF1 and Id3. Nfil3⁺ Klrg1⁺ subset is considered a more mature stage of tissue Treg precursors in the SLOs. Upon arriving at each tissue, Treg cells undertake a further differentiation process mediated by tissue local factors. For instance, PPARγ drives phenotypic and functional maturation of adipose tissue Treg cells, and Blipm1 drives intestinal Treg cells to produce IL-10. Of note, the development of Tfr cells occurs at a relatively earlier stage, prior to the “turning-off” of TCF1, LEF1, or Id3