SUMMARY 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-I-restricted CD4+Foxp3+ Treg (CI-Treg) cells. Blocking T-cell-intrinsic TGFβ signaling diminished CI-Treg populations in lamina propria but did not preclude the CD8-to-CD4 conversion. Microbiota were not required for the cross-differentiation but 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 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.

No abstract

Peripheral regulatory T cells engage in a necessary role in maintaining the volatile balance between the normal flora of the gut and the host immune system. However, the clonal origin of peripheral Treg cells is not well understood and has proven difficult to elucidate in the presence of naturally occurring thymic Treg cells. We hypothesized that the gut-associated environment enables cross differentiation of the CD8 T cell lineage to CD4 Treg cells for the regulation of immune cell homeostasis. Our preliminary examination found evidence for cross-differentiation from the CD8 lineage to CD4 effector and regulatory T cells. Further studies showed that these cross-differentiated CD4 Treg cells were effective in protecting from intestinal inflammatory damage. We found that in transfer experiments mature CD8 T cells were capable of cross-differentiating into CD4 T cells. Results from normal flora depletion studies by broad spectrum antibiotics showed that cross-differentiation of CD8 T cells into CD4 T cells was dependent on the normal flora of the gut. The results that we have obtained suggest that CD8 T cells have the potential to cross-differentiate into CD4 T cells and Treg cells. This pathway may participate in regulating and maintaining the fine balance of tolerance and immunity between normal flora and host immune system.