Intestinal CD4−CD8αβ−TCRαβ+ T cells function as tolerogenic antigen presenting cells in mice

Yasuhiro Nemoto (), Ryo Morikawa, Yuki Yonemoto, Shohei Tanaka, Yuria Takei, Shigeru Oshima, Takashi Nagaishi, Kiichiro Tsuchiya, Tetsuya Nakamura, Kento Takenaka, Kazuo Ohtsuka, Xigui Chen, Hitoshi Okazawa, Ryuichi Okamoto, Mamoru Watanabe and Ulrich H. Andrian ()
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Yasuhiro Nemoto: Institute of Science Tokyo
Ryo Morikawa: Institute of Science Tokyo
Yuki Yonemoto: Institute of Science Tokyo
Shohei Tanaka: Institute of Science Tokyo
Yuria Takei: Institute of Science Tokyo
Shigeru Oshima: Institute of Science Tokyo
Takashi Nagaishi: Institute of Science Tokyo
Kiichiro Tsuchiya: Institute of Science Tokyo
Tetsuya Nakamura: Institute of Science Tokyo
Kento Takenaka: Institute of Science Tokyo
Kazuo Ohtsuka: Institute of Science Tokyo
Xigui Chen: Institute of Science Tokyo
Hitoshi Okazawa: Institute of Science Tokyo
Ryuichi Okamoto: Institute of Science Tokyo
Mamoru Watanabe: Institute of Science Tokyo
Ulrich H. Andrian: Harvard Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract The intestinal mucosa harbors diverse lymphocyte populations, including double negative CD4–CD8αβ–TCRαβ+ T (DNT) cells, in the intraepithelial compartment and the lamina propria. Here we report that DNT cells in mouse small intestines are motile and reach across the epithelial barrier to capture luminal antigens (Ags). DNT cells then migrate to mesenteric lymph nodes (MLN) and upregulate MHC-II, as evidenced by a sizeable fraction of mouse DNT cells in Peyer’s patches (PP) and MLN expressing MHC-II but little or no co-stimulatory molecules. Functionally, the presentation of intestinal antigens by DNT cells tolerizes antigen-specific naive CD4+ T cells, with this tolerization reversed by conditional ablation of MHC-II in T cells, thereby rendering mutant mice hypersusceptible to intestinal inflammation. Intriguingly, intestinal T cells in patients with Crohn’s disease also express lower levels of HLA-DR than those in healthy controls. Our findings thus potentially implicate MHC-II+ DNT cells in intestinal immune homeostasis and pathogenesis of inflammatory bowel disease.

Date: 2025
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DOI: 10.1038/s41467-025-62089-y

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