CD4 and CD8 Tcell lineages differentiate through respective thymic selection processes. Here, we report cross-differentiation from the CD8 lineage toCD4 Tcells, but not vice versa, predominantly in the large-intestine-associated microenvironment. It occurred in the absence or distal presence of cognate antigens. This pathway produced MHC-class-I-restricted CD4+Foxp3+ Treg (CI-Treg) cells. Blocking Tcell-intrinsic TGFβ signaling diminished CI-Treg populations in lamina propria, but it did not preclude the CD8-to-CD4 conversion. Microbiota were not required for the cross-differentiation, but the presence of microbiota led to expansion of the converted CD4 Tcell population in the large intestine. CI-Treg cells did not promote tolerance to microbiota per se, but they regulated systemic homeostasis of T lymphocytes and protected the large intestine from inflammatory damage. Overall, the clonal conversion from the CD8 lineage to CD4 Tcell subsets occurred regardless of "self" or "nonself." This lineage plasticity may promote "selfless" tolerance for immune balance.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)