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MHC class I (MHC-I)-restricted CD4 + T cells have long been discovered in the natural repertoire of healthy humans as well as patients with autoimmune diseases or cancer, but the exact origin of these cells remains to be fully characterized. In mouse models, mature peripheral CD8 + T cells have the potential to convert to CD4 + T cells in the mesenteric lymph nodes. This conversion can produce a unique population of MHC-I-restricted CD4 + T cells including Foxp3 + regulatory T cells termed MHC-I-restricted CD4 + Foxp3 + T (CI-T reg ) cells. In this study we examined the cellular and molecular elements that promote CD8-to-CD4 lineage conversion and the development of CI-T reg cells in mice. Using adoptive transfer and bone marrow chimera experiments, we found that the differentiation of CI-T reg cells was driven by lymph node stromal cell (LNSC)-intrinsic MHC-II expression as opposed to transcytosis of MHC-II from bone marrow-derived APCs. The lineage conversion was accompanied by Runx3 versus ThPOK transcriptional switch. This finding of a new role for LNSCs in vivo led us to develop an efficient tissue culture method using LNSCs to generate and expand CI-T reg cells in vitro. CI-T reg cells expanded in vitro with LNSCs effectively suppressed inflammatory tissue damage caused by pathogenic CD4 + T cells in mouse models of colitis. This study identified a novel role of MHC-II expressed by LNSCs in immune regulation and the potential utilization of LNSCs to generate novel subsets of immune regulatory cells for therapeutic applications.

Lymph Node Stromal Cell–Intrinsic MHC Class II Expression Promotes MHC Class I–Restricted CD8 T Cell Lineage Conversion to Regulatory CD4 T Cells