Premium
Dysfunctional CD39 POS regulatory T cells and aberrant control of T‐helper type 17 cells in autoimmune hepatitis
Author(s) -
Grant Charlotte R.,
Liberal Rodrigo,
Holder Beth S.,
Cardone John,
Ma Yun,
Robson Simon C.,
MieliVergani Giorgina,
Vergani Diego,
Longhi Maria Serena
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26583
Subject(s) - proinflammatory cytokine , autoimmune hepatitis , immunology , effector , interleukin 7 receptor , hepatology , biology , t cell , medicine , il 2 receptor , hepatitis , inflammation , immune system
Autoimmune hepatitis (AIH) is an important cause of severe liver disease and is associated with both quantitative and qualitative regulatory T‐cell (Treg) impairments. Tregs express CD39, an ectonucleotidase responsible for extracellular nucleotide hydrolysis, culminating in the production of immunosuppressive adenosine. Here, we describe multiple CD39 pos Treg defects that potentially contribute to the impaired immunoregulation that is characteristic of AIH. We have examined the frequency and phenotype of CD39 pos Tregs by flow cytometry and measured their ectonucleotidase activity. The capacity of CD4 pos CD25 high , CD4 pos CD25 high CD39 pos , and CD4 pos CD25 high CD39 neg subsets to suppress both proliferation of effector T cells and interleukin (IL)‐17 production was evaluated. In AIH, CD39 pos Tregs are decreased in frequency, exhibit limited adenosine triphosphate/adenosine diphosphate hydrolysis activity, and fail to suppress IL‐17 production by effector CD4 T cells. Moreover, these CD39 pos Tregs display a more proinflammatory profile in AIH, which is characterized by elevated CD127 positivity, and a greater propensity to produce interferon‐gamma or IL‐17 upon challenge with proinflammatory stimuli. Conclusions : In AIH, CD39 pos Tregs are decreased in number, fail to adequately hydrolyze proinflammatory nucleotides and do not efficiently suppress IL‐17 production by effector CD4 T cells. CD39 pos Tregs show plasticity and are unstable upon proinflammatory challenge, suggesting that defective immunoregulation in AIH might result not only from reduced Treg number and function, but also from increased conversion of Tregs into effector cells. (H epatology 2014;59:1007–1015)