A study by Badr and colleagues showed that self-reactive CD8 T cells left early from the thymus and became PD-1-positive CD8 T cells in the periphery that are tolerant to self-antigens [1]. This report is reminiscent of an earlier study on self-reactive CD4 T cells eventually becoming CD4 T regulatory cells after negative selection in the thymus with high expression of the inhibitory receptor CTLA4 on the cell surface [2]. Thus, a new picture emerges, showing that self-reactive T cells in the thymus disappear after negative selection and reappear in the periphery with different identities: the regulatory T cells. Interestingly, it seems that medulla dendritic cells (mDCs) and thymus-homing T cells (from circulation) are required to generate peripheral Tregs (pTregs) to build up tolerance against foreign antigens as well as some tissue-specific host antigens. A recent interesting discovery showed that the AIRE-expressing Thetis cell family, which is essential for the formation of pTregs [3], could be tissue-specific cells migrating back from the periphery, similar to previously reported Mimetic cells [4]. Furthermore, CD8 Treg could likely be the same population of tumor-infiltrating CD8 T cells, which is currently termed terminally differentiated exhausted CD8 T cells. Finally, the picture of regulatory T cells, including CD4 Treg and CD8 Treg, could be drawn, accounting for both branches of the T cell family.

CD8 Treg, CD4 Treg, CD25, IL-15R, TGF-beta, FOXO1, FOXP3, PD-1, CTLA4, IL-10, Thetis cells (TCs)