Cross-Differentiation from the CD8 Lineage to CD4 T Cells in the Gut-Associated Microenvironment with a Nonessential Role of Microbiota

CD4 and CD8 T cell lineages differentiate through respective thymic selection processes. Here, we report cross-differentiation from the CD8 lineage to CD4 T cells, 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-Irestricted CD(4+)Foxp(3+) Treg (CI-T-reg) cells. Blocking T cell-intrinsic TGF beta signaling diminished CI-T-reg 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 T cell population in the large intestine. CI-Treg cells did not promote tolerance to microbiota per se, but they regulatedsystemichomeostasis of T lymphocytes and protected the large intestine from inflammatory damage. Overall, the clonal conversion from the CD8 lineage to CD4 T cell subsets occurred regardless of self or nonself. This lineage plasticity may promote selfless tolerance for immune balance.