Hu & Zhang Lab
The State Key Laboratory of Biotherapy Si-Chuan University

Affinity for self antigen selects Treg cells with distinct functional properties

Treg cells play a dominant role in self tolerance and immune homeostasis. Based on cell surface markers and function, Treg cells are divided into different subsets. But the differentiation and development mechanism of  Treg subsets is not fully understood. In this article, Lena Wyss et al characterize two Treg cells subsets with different surface markers and self-reactive, distinct TCR repertoires and regulatory functions.

Based on the expression of  GITR, PD-1 and CD25, Treg cells in LNs, spleen and thymus are identified as Triple-high (GITR-high/PD-1high/CD25high) Treg cells and  Triple-low (GITRlow/PD-1low/CD25low) Treg cells. Triple-high and Triple-low Treg cells are exclusively generated through recognition of self antigens. Deep sequencing results indicate that Triple-high Treg cells, Triple-low Treg cells and CD4+ Tconv cells have distinct TCR repertoires, indicating TCR specificity is crucial for determining these Treg cells subtypes. Triple-high and Triple-low Treg cells are developed by exposing to negatively selecting antigens, Triple-high Treg cells show higher self-reactive than Triple-low Treg cells. Therefore, during development in thymus, Treg cells phenotype is determined by the affinity of its TCR for self antigen. Triple-high and Triple-low Treg cells show distinct regulatory properties. Triple-high Treg cells  control lymphocyte proliferation in peripheral LNs. Meanwhile Triple-low Treg cells suppress the development of naïve CD4+ Tconv cells induced colitis by promoting the conversion of CD4+Tconv cells into iTreg cells. Foxp3-deficient (Scurfy) mice contained Foxp3- Triple-high like and Foxp3- Triple-low like CD4+ T cells with distinct pathological properties. Scurfy Triple-high CD4+ T cells infiltrate the skin, whereas Scurfy Triple-low CD4+ T cells induced colitis and wasting disease.

In summary, affinity for self antigen underlies the development of two distinct populations of regulatory T cells. The highly self-reactive Triple-high Treg cells control the homeostatic proliferation of lymphocytes in peripheral LNs, whereas the lowly self-reactive Triple-low Treg cells facilitate the generation of  iTreg cells to maintain lymphocyte homeostasis in the colon.

by Liangbin