Analysis of unconventional T cells as novel antigen presenting cells

• Project/Area Number: 17K09371
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Nemoto Yasuhiro 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (20456213)
• Co-Investigator(Kenkyū-buntansha): 渡辺 守 東京医科歯科大学, 高等研究院, 特別栄誉教授 (10175127)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 腸管免疫 / 腸管上皮間細胞 / double negative T細胞 / 抗原提示細胞 / クローン病 / 上皮間リンパ球 / CD4-CD8αβ-T細胞 / Double Negative T細胞 / γδT細胞

Outline of Final Research Achievements

Here, we show that murine DNTs in the small intestine (SI) reach across the epithelial barrier to capture luminal antigens. A sizeable fraction of DNTs in Peyer’s patches (PPs), Mesenteric lymph nodes (MLNs) and among LPLs, but not among IELs, express MHC-II, but little or no classical co-stimulatory molecules, suggesting that DNT-mediated antigen presentation to naive CD4+ T cells may trigger tolerogenic rather than effector responses. Indeed, DNTs acquire, process and present antigenic proteins and anergize antigen-specific CD4+ T cells. Surprisingly, ex vivo antigen presentation experiment showed that DNTs were the most effective intestinal antigen uptake/process/presentation pathway in PP. Conditional genetic ablation of MHC-II in T cells disabled this suppressive function and rendered mutant mice hypersusceptible to DSS colitis.

Academic Significance and Societal Importance of the Research Achievements

本検討ではこれまであまり機能の分かっていなかったDNT細胞のユニークな特徴を明らかにした。DNT細胞は遺伝子的にはγδT細胞に非常に似ており、形態的にはアメーバ様で高い運動能を有し、MHC-IIを発現し、高い抗原取り込み能、抗原提示能を有する。腸管粘膜免疫機構がいかにして抗原に対して炎症と免疫寛容を振り分けるのかという粘膜免疫機構における最重要命題の一端が明らかになるのみならず、炎症性腸疾患、食物アレルギー、大腸癌などの病態生理と新規治療法、有効な粘膜免疫ワクチンの開発に繋がる可能性がある。