CD39 mediated regulation of Th17-cell effector function is impaired in juvenile autoimmune liver disease

Rodrigo Liberal, Charlotte R. Grant, Yun Ma, Eva Csizmadia, Zhenghui Gordon Jiang, Michael A. Heneghan, Eric U. Yee, Giorgina Mieli-Vergani, Diego Vergani, Simon C. Robson, Maria Serena Longhi

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Background & aims: T-helper-type 17 (Th17) cells are involved in autoimmune tissue damage. CD39 is an ectonucleotidase that catalyzes extracellular ATP/ADP hydrolysis, culminating in the generation of immunosuppressive adenosine. Functional CD39 expression confers immunosuppressive properties upon immune cells. As the proportion of CD39 lymphocytes is decreased in juvenile autoimmune liver disease (AILD), we have explored whether decreased CD39 expression is present on Th17 cells and whether this phenomenon is associated with heightened effector function and inflammation. 
Methods: Thirty-eight patients with juvenile AILD (22 autoimmune hepatitis and 16 autoimmune sclerosing cholangitis), 8 disease controls (DC) and 16 healthy subjects (HS) were studied. Peripheral blood cell phenotype was determined by flow cytometry; ability to suppress by inhibition of cell proliferation/ effector cytokine production; ectoenzymatic activity by thin layer chromatography; expression of adenosine receptor, adenosine deaminase (ADA) and phosphodiesterases (PDE) by quantitative real-time PCR or by Western Blot. 

Results: CD39þ Th17 (Th17CD39þ) cells from HS appear activated and contain high frequencies of lymphocytes producing regulatory cytokines. In AILD, however, Th17CD39þ cells are markedly diminished and fail to generate AMP/adenosine, thereby limiting control of both target cell proliferation and IL-17 production. When compared to HS, Th17 cells from AILD patients also show lower A2A adenosine receptor expression while displaying similar levels of PDE4A, PDE4B and ADA. Only rare Th17CD39þ cells are observed by liver immunohistochemistry. 
Conclusions: Th17CD39þ cells in juvenile AILD are both quantitatively decreased and qualitatively deficient. Low levels CD39 and A2A expression may contribute to the perpetuation of Th17 cell effector properties and unfettered inflammation in this disease.
Original languageEnglish
Pages (from-to)102-112
JournalJournal of Autoimmunity
Issue number0
Early online date20 May 2016
Publication statusPublished - 20 May 2016


  • Th17 cells
  • CD39
  • Adenosine
  • ATP
  • Autoimmune liver disease


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