1. Laboratory of Immune Regulation, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
2. Yakult Central Institute for Microbiological Research, Yaho 1796, Kunitachi, Tokyo 186-8650, Japan
3. WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
4. Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
5. Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
6. Department of Cell Physiology and Pharmacology, Henry Wellcome Building 2/59b, University of Leicester, Leicester LE1 9HN, UK
7. These authors contributed equally to this work.

Correspondence to: Kenya Honda^1,3Kiyoshi Takeda^1,3 Correspondence and requests for materials should be addressed to K.H. (Email: honda@ongene.med.osaka-u.ac.jp) or K.T. (Email: ktakeda@ongene.med.osaka-u.ac.jp).

Abstract

Interleukin (IL)-17-producing CD4⁺ T lymphocytes (T_H17 cells) constitute a subset of T-helper cells involved in host defence and several immune disorders^{1, 2}. An intriguing feature of T_H17 cells is their selective and constitutive presence in the intestinal lamina propria³. Here we show that adenosine 5'-triphosphate (ATP) that can be derived from commensal bacteria activates a unique subset of lamina propria cells, CD70^highCD11c^low cells, leading to the differentiation of T_H17 cells. Germ-free mice exhibit much lower concentrations of luminal ATP, accompanied by fewer lamina propria T_H17 cells, compared to specific-pathogen-free mice. Systemic or rectal administration of ATP into these germ-free mice results in a marked increase in the number of lamina propria T_H17 cells. A CD70^highCD11c^low subset of the lamina propria cells expresses T_H17-prone molecules, such as IL-6, IL-23p19 and transforming-growth-factor--activating integrin-V and -8, in response to ATP stimulation, and preferentially induces T_H17 differentiation of co-cultured naive CD4⁺ T cells. The critical role of ATP is further underscored by the observation that administration of ATP exacerbates a T-cell-mediated colitis model with enhanced T_H17 differentiation. These observations highlight the importance of commensal bacteria and ATP for T_H17 differentiation in health and disease, and offer an explanation of why T_H17 cells specifically present in the intestinal lamina propria.

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