Dysfunctional CD39^POSregulatory T cells and aberrant control of T-helper type 17 cells in autoimmune hepatitis

Abstract

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. (HEPATOLOGY 2014;59:1007-1015 See Editorial on Page 754A utoimmune hepatitis (AIH) is an inflammatory disease of the liver, characterized by female preponderance, interface hepatitis on histology, hypergammaglobulinemia, and serum autoantibody positivity. 1,2 Several lines of evidence indicate that in AIH, numerical and functional regulatory T-cell (Treg) defects are likely to play a permissive pathogenic role, allowing effector CD4 and CD8 T lymphocytes to initiate and perpetuate liver damage. [3][4][5] The reasons for Treg functional impairment in AIH are unclear. Previous studies in both mice and humans

Autoimmune hepatitis

“…Recent studies suggested that the pathogenic activities of effector T cells in both types 1 and 2 AIH result from decreases in quantities and functional capacities of autoantigen-specific CD4 T regulatory (Treg) cells required to inhibit the autoimmune effector cell response(s) [36][37][38]. However, the role of Treg dysfunction remains controversial, since others failed to detect dysfunctional Tregs in AIH [39].…”

Bilirubin suppresses Th17 immunity in colitis by upregulating CD39

“…A malachite green assay was performed as previously described (51). The concentration of free phosphate was measured in the supernatant of Th17 cell cultures using the colorimetric Sensolyte Malachite Green Phosphate Assay kit (AnaSpec).…”

Distinct roles of ecto-nucleoside triphosphate diphosphohydrolase-2 (NTPDase2) in liver regeneration and fibrosis

“…In the liver, CD39 (NTPDase1) is expressed on Kupffer cells, other sinusoidal immune cells, and vascular endothelium and is known to have immunoregulatory functions in inflammatory diseases, such as autoimmune hepatitis [23]. In contrast to CD39, NTPDase2 expression in the healthy liver is substantially less abundant and limited to periductal and perivascular fibrocytic cells in portal areas.…”