Introduction In autoimmune hepatitis (AIH) CD4posCD25high regulatory T-cells (T-regs), a subset central to immune-tolerance, are numerically defective and impaired in their ability to control effector cell function. At variance with CD4 effectors, T-regs, classically known as CD25high and FOXP3pos, express low levels of the activation marker CD127. The aim of the current study was to provide a phenotypic and functional profile of CD4posCD25highCD127lowT-regs (CD127lowT-regs) in AIH and to explore to what extent absence or low levels of CD127 impact on T-reg ability to suppress.
Methods 20 ANA/SMA+ AIH patients and 12 healthy subjects (HS) were studied. T-reg phenotype was determined by flow cytometry using antibodies to CD4, CD25, CD127, CTLA-4 and Galectin-9, a molecule linked to T-reg ability to suppress. T-reg transcription factor and cytokine profile were assessed by intracellular staining. CD127lowT-reg ability to suppress was evaluated in a proliferation assay following co-culture with CD25neg target cells.
Results In AIH CD4posCD25high cells contained fewer CD127low cells than in HS. Compared to conventional CD4posCD25high (cT-regs), CD127lowT-regs from both AIH and HS had a) higher numbers of FOXP3pos, CTLA-4pos, Galectin-9pos and IL-10pos cells; b) lower numbers of T-betpos, RORCpos, IFNgpos and IL-17pos cells; and c) similar numbers of TGF-bpos cells. In AIH, CD127lowT-regs contained fewer FOXP3pos, CTLA-4pos, Galectin-9pos, IL-10pos and TGF-bpos cells and higher frequencies of T-betpos, RORCpos, IFNgpos and IL-17pos cells than in HS. CD127lowT-regs inhibited CD25neg cell proliferation more effectively than cT-regs, though less markedly in AIH than in HS. In AIH, treatment with anti-IFNg and anti-IL-17 neutralising antibodies ameliorated the suppressive ability of cT-regs, while leaving unchanged that of CD127lowT-regs; exposure to anti-IL-10 neutralising antibodies reduced cT-reg suppression in HS, but not in AIH.
Conclusion CD127low T-regs bear the phenotypic and functional signature of “true T-regs”. Low numbers and reduced suppressive function of CD127lowT-regs in AIH may contribute to breakdown of immune-tolerance by permitting effector cells to perpetrate hepatocyte damage.
Competing interests None declared.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.