Abstract
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(+) T(reg) (CI-T(reg)) 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-T(reg) 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.
Highlights
The development of the immune system has been largely characterized on the basis of discriminating “self”, the host’s own cells, from “nonself”, exemplified by infectious microbes, towards an outcome of either tolerance or immunity (Burnet, 1957)
OT1+Rago mice on the C57BL/6 (B6) genetic background, a widely used model in immunological studies, are thought to harbor a monoclone of CD8 T cells with T-cell antigen receptor (TCR) restricted to MHC-class-I recognition
We found a large population of CD4 T cells (~10–20%) in the large intestine lamina propria (LILP), with a vast majority expressing Foxp3, the transcription factor specifying the CD4+ Treg cell lineage (Fontenot et al, 2003; Hori et al, 2003; Khattri et al, 2003)
Summary
The development of the immune system has been largely characterized on the basis of discriminating “self”, the host’s own cells, from “nonself”, exemplified by infectious microbes, towards an outcome of either tolerance or immunity (Burnet, 1957). The innate immune system discriminates microbial agents by patterns that are distinct from eukaryotic cells, whereas the adaptive immune system is armed with a repertoire of T and B lymphocyte clones with fine specificity to foreign antigens but is tolerant toward the host’s “self” tissue. Treg cell clones specific to microbial agents in the large intestine were identified, and the unique repertoire of colonic Treg cells suggested that the differentiation of peripheral Treg cells could occur locally at the intestinal mucosal surface (Lathrop et al, 2011). Sequencing analyses of the T-cell antigen receptor (TCR) of colonic Treg cells using the TCRmini model, which was constructed to host a diverse but limited repertoire to enable the sequencing studies, suggested that thymus-derived Treg cells may be mainly responsible for tolerance induction to the large intestine microbiota (Cebula et al, 2013)
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