ATP drives lamina propria T_H17 cell differentiation

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. An intriguing feature of T_H17 cells is their selective and constitutive presence in the intestinal lamina propria. 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-β-activating integrin-αV and -β8, 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.