Potential conflict of interest: nothing to report.
Autoimmune, Cholestatic and Biliary Disease
Dysfunctional CD39POS regulatory T cells and aberrant control of T-helper type 17 cells in autoimmune hepatitis
Article first published online: 30 JAN 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 59, Issue 3, pages 1007–1015, March 2014
How to Cite
Grant, C. R., Liberal, R., Holder, B. S., Cardone, J., Ma, Y., Robson, S. C., Mieli-Vergani, G., Vergani, D. and Longhi, M. S. (2014), Dysfunctional CD39POS regulatory T cells and aberrant control of T-helper type 17 cells in autoimmune hepatitis. Hepatology, 59: 1007–1015. doi: 10.1002/hep.26583
See Editorial on Page 754
The authors acknowledge financial support from the Department of Health by the National Institute for Health Research (NIHR) comprehensive Biomedical Research Center award to Guy's & St Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust. C.R.G. is supported by an Alex P Mowat Ph.D. Studentship from King's College Hospital Charity, UK. R.L. is supported by a doctoral grant from the Science and Technology Foundation, Science and Higher Education Ministry, Portugal. M.S.L. was supported by the Roger Dobson Fund, King's College Hospital Charity, UK, when this project was started and is currently supported by a Clinician Scientist Fellowship from the Medical Research Council, UK.
- Issue published online: 25 FEB 2014
- Article first published online: 30 JAN 2014
- Accepted manuscript online: 20 JUN 2013 08:22AM EST
- Manuscript Accepted: 6 JUN 2013
- Manuscript Received: 26 MAR 2013
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 CD39pos Treg defects that potentially contribute to the impaired immunoregulation that is characteristic of AIH. We have examined the frequency and phenotype of CD39pos Tregs by flow cytometry and measured their ectonucleotidase activity. The capacity of CD4posCD25high, CD4posCD25highCD39pos, and CD4posCD25highCD39neg subsets to suppress both proliferation of effector T cells and interleukin (IL)-17 production was evaluated. In AIH, CD39pos 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 CD39pos 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, CD39pos Tregs are decreased in number, fail to adequately hydrolyze proinflammatory nucleotides and do not efficiently suppress IL-17 production by effector CD4 T cells. CD39pos 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)