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ATP drives lamina propria TH17 cell differentiation

Abstract

Interleukin (IL)-17-producing CD4+ T lymphocytes (TH17 cells) constitute a subset of T-helper cells involved in host defence and several immune disorders1,2. An intriguing feature of TH17 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, CD70highCD11clow cells, leading to the differentiation of TH17 cells. Germ-free mice exhibit much lower concentrations of luminal ATP, accompanied by fewer lamina propria TH17 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 TH17 cells. A CD70highCD11clow subset of the lamina propria cells expresses TH17-prone molecules, such as IL-6, IL-23p19 and transforming-growth-factor-β-activating integrin-αV and -β8, in response to ATP stimulation, and preferentially induces TH17 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 TH17 differentiation. These observations highlight the importance of commensal bacteria and ATP for TH17 differentiation in health and disease, and offer an explanation of why TH17 cells specifically present in the intestinal lamina propria.

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Figure 1: Administration of ATP leads to a marked increase in lamina propria T H 17 cells in otherwise T H 17-lacking germ-free mice.
Figure 2: ATP induces differentiation of naive CD4 + T cells into T H 17 cells.
Figure 3: A unique subset of lamina propria CD11c + cells express P2X and P2Y receptors.
Figure 4: Treatment with ATP exacerbates experimental colitis induced by adoptive transfer of naive CD4 + T cells.

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Acknowledgements

We thank A. Iwasaki and N. Tsuji for discussion, M. H. Jang, H. Ohno, H. Yamane, M. Yoshida and H. Shiomi for technical advice and reagents, and J. Borst for CD27-deficient mice. This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, the Ministry of Health, Labour and Welfare, the Osaka Foundation for the Promotion of Clinical Immunology, the Ichiro Kanehara Foundation, Sumitomo Foundation, Senri Life Science Foundation and the Naito Foundation.

Author Contributions K.H. conceived the research, planned experiments and analyses and wrote the paper; K.A. and J.N. largely conducted experiments; T.S. performed some of the experiments; Y.U., M.Y., M.O., H.Y., N.I. and R.E. provided key materials; and K.T. oversaw the whole project.

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Correspondence to Kenya Honda or Kiyoshi Takeda.

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Atarashi, K., Nishimura, J., Shima, T. et al. ATP drives lamina propria TH17 cell differentiation. Nature 455, 808–812 (2008). https://doi.org/10.1038/nature07240

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