Purinergic Signaling as a Regulator of Th17 Cell Plasticity.
T helper type 17 (Th17) lymphocytes, characterized by the production of interleukin-17 and other pro-inflammatory cytokines, are present in intestinal lamina propria and have been described as important players driving intestinal inflammation. Recent evidence, supporting the notion of a functional and phenotypic instability of Th17 cells, has shown that Th17 differentiate into type 1 regulatory (Tr1) T cells during the resolution of intestinal inflammation. Moreover, it has been suggested that the expression of CD39 ectonucleotidase endows Th17 cells with immunosuppressive properties. However, the exact role of CD39 ectonucleotidase in Th17 cells has not been studied in the context of intestinal inflammation. Here we show that Th17 cells expressing CD39 ectonucleotidase can hydrolyze ATP and survive to ATP-induced cell death. Moreover, in vitro-generated Th17 cells expressing the CD39 ectonucleotidase produce IL-10 and are less pathogenic than CD39 negative Th17 cells in a model of experimental colitis in Rag-/- mice. Remarkably, we show that CD39 activity regulates the conversion of Th17 cells to IL-10-producing cells in vitro, which is abrogated in the presence of ATP and the CD39-specific inhibitor ARL67156. All these data suggest that CD39 expression by Th17 cells allows the depletion of ATP and is crucial for IL-10 production and survival during the resolution of intestinal inflammation.
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Dominique
D
Fernández
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Felipe
F
Flores-Santibáñez
Facultad de Ciencias Biologicas, Universidad Andres Bello, Santiago, Chile.|Fundacion Ciencia & Vida, Santiago, Chile.
Jocelyn
J
Neira
Fundacion Ciencia & Vida, Santiago, Chile.
Francisco
F
Osorio-Barrios
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Gabriela
G
Tejón
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Sarah
S
Nuñez
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Yessia
Y
Hidalgo
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Maria Jose
MJ
Fuenzalida
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Daniel
D
Meza
Fundacion Ciencia & Vida, Santiago, Chile.
Gonzalo
G
Ureta
Fundacion Ciencia & Vida, Santiago, Chile.
Alvaro
A
Lladser
Facultad de Ciencias Biologicas, Universidad Andres Bello, Santiago, Chile.|Fundacion Ciencia & Vida, Santiago, Chile.
Rodrigo
R
Pacheco
Departamento de Biologia y Centro de Biotecnologia Acuicola (CBA), Facultad de Quimica y Biologia, Universidad de Santiago de Chile, Santiago, Chile.
Claudio
C
Acuña-Castillo
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Victoria
V
Guixé
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Francisco J
FJ
Quintana
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Maria Rosa
MR
Bono
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.|Facultad de Ciencias Biologicas, Universidad Andres Bello, Santiago, Chile.|Fundacion Ciencia & Vida, Santiago, Chile.
Mario
M
Rosemblatt
Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.
Daniela
D
Sauma
D015720:5'-Nucleotidase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001081:Apyrase / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003092:Colitis / Q000276:immunology / Q000473:pathology; D006868:Hydrolysis; D007249:Inflammation / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011983:Receptors, Purinergic / Q000378:metabolism*; D015398:Signal Transduction; D058504:Th17 Cells / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D015703:Antigens, CD; D053759:Interleukin-23; D011983:Receptors, Purinergic; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D007371:Interferon-gamma; D000255:Adenosine Triphosphate; D015720:5'-Nucleotidase; D001081:Apyrase; C067869:CD39 antigen