ATP drives lamina propria T(H)17 cell differentiation.
Interleukin (IL)-17-producing CD4(+) T lymphocytes (T(H)17 cells) constitute a subset of T-helper cells involved in host defence and several immune disorders. An intriguing feature of T(H)17 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(high)CD11c(low) cells, leading to the differentiation of T(H)17 cells. Germ-free mice exhibit much lower concentrations of luminal ATP, accompanied by fewer lamina propria T(H)17 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(H)17 cells. A CD70(high)CD11c(low) subset of the lamina propria cells expresses T(H)17-prone molecules, such as IL-6, IL-23p19 and transforming-growth-factor-beta-activating integrin-alphaV and -beta8, in response to ATP stimulation, and preferentially induces T(H)17 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(H)17 differentiation. These observations highlight the importance of commensal bacteria and ATP for T(H)17 differentiation in health and disease, and offer an explanation of why T(H)17 cells specifically present in the intestinal lamina propria.
Atarashi
Koji
K
Laboratory of Immune Regulation, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Nishimura
Junichi
J
Shima
Tatsuichiro
T
Umesaki
Yoshinori
Y
Yamamoto
Masahiro
M
Onoue
Masaharu
M
Yagita
Hideo
H
Ishii
Naoto
N
Evans
Richard
R
Honda
Kenya
K
Takeda
Kiyoshi
K
D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D039521:CD11c Antigen / Q000378:metabolism; D053282:CD27 Ligand / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D005243:Feces / Q000382:microbiology; D005260:Female; D005856:Germ-Free Life; D007070:Immunoglobulin A / Q000032:analysis / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D009092:Mucous Membrane / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology
D039521:CD11c Antigen; D053282:CD27 Ligand; D007070:Immunoglobulin A; D020381:Interleukin-17; D018048:Receptors, Purinergic P2; D000255:Adenosine Triphosphate