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

•CD8-to-CD4 cross-differentiation occurs with the same clonotypic T cell receptor•This conversion produces MHC-class-I-restricted CD4+Foxp3+ Treg (CI-Treg) cells•CD4+ CI-Treg cells are generated in mesenteric lymph nodes without regard to “self”•Microbiota expand the converted population but are dispensable for its generation

SummaryCD4 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-I-restricted CD4+Foxp3+ Treg (CI-Treg) cells. Blocking T cell-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 T cell 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 T cell subsets occurred regardless of “self” or “nonself.” This lineage plasticity may promote “selfless” tolerance for immune balance.

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