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.

MHC I 类 (MHC-I) 限制性 CD4 ⁺ T 细胞早已在健康人类以及自身免疫性疾病或癌症患者的天然细胞库中被发现，但这些细胞的确切来源仍有待充分表征。在小鼠模型中，成熟的外周 CD8 ⁺ T 细胞有可能在肠系膜淋巴结中转化为 CD4 ^{+ T 细胞。}这种转化可以产生独特的 MHC-I 限制性 CD4 ⁺ T 细胞群，包括 Foxp3 ⁺调节性 T 细胞，称为 MHC-I 限制性 CD4 ⁺ Foxp3 ⁺ T (CI-T _reg） 细胞。在这项研究中，我们检查了促进 CD8 向 CD4 谱系转换和小鼠 CI-T _reg细胞发育的细胞和分子元素。使用过继转移和骨髓嵌合体实验，我们发现 CI-T _reg细胞的分化是由淋巴结基质细胞 (LNSC) 内在的 MHC-II 表达驱动的，而不是来自骨髓来源的 APC 的 MHC-II 胞吞作用。 . 谱系转换伴随着 Runx3 与 ThPOK 转录开关。这一发现 LNSC 在体内的新作用使我们开发了一种有效的组织培养方法，使用 LNSC 在体外生成和扩增 CI-T _reg细胞。CI-T_注册用LNSCs体外扩增的细胞有效抑制了结肠炎小鼠模型中由致病性CD4 ^{+ T细胞引起的炎症组织损伤。}本研究确定了 LNSCs 表达的 MHC-II 在免疫调节中的新作用，以及 LNSCs 的潜在利用来产生用于治疗应用的新型免疫调节细胞亚群。