These authors contributed equally to this work.
Autoimmune, Cholestatic and Biliary Disease
Article first published online: 6 JUL 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 2, pages 677–686, August 2012
How to Cite
Liberal, R., Grant, C. R., Holder, B. S., Ma, Y., Mieli-Vergani, G., Vergani, D. and Longhi, M. S. (2012), The impaired immune regulation of autoimmune hepatitis is linked to a defective galectin-9/tim-3 pathway. Hepatology, 56: 677–686. doi: 10.1002/hep.25682
Potential conflict of interest: Nothing to report.
Rodrigo Liberal is supported by a doctoral grant from the Science and Technology Foundation, Science and Higher Education Ministry, Portugal; Giorgina Mieli-Vergani is supported by WellChild, Cheltenham, United Kingdom, and the Children's Liver Disease Foundation, Birmingham, United Kingdom; Maria Serena Longhi was supported by the Roger Dobson Fund, King's College Hospital Charity, United Kingdom, when this project was started and is currently supported by a Clinician Scientist Fellowship from the Medical Research Council, United Kingdom.
- Issue published online: 25 JUL 2012
- Article first published online: 6 JUL 2012
- Accepted manuscript online: 28 FEB 2012 12:16AM EST
- Manuscript Accepted: 15 FEB 2012
- Manuscript Received: 16 DEC 2011
In autoimmune hepatitis (AIH), liver-damaging CD4 T cell responses are associated with defective CD4posCD25pos regulatory T cells (T-regs). Galectin-9 (Gal9), a β-galactosidase–binding protein expressed by T-regs, is key to their function, inhibiting T helper 1 immune responses by binding T cell immunoglobulin and mucin domain 3 (Tim-3) on CD4 effector cells. We investigated whether impaired immunoregulation in AIH results from reduced expression of Gal9 in T-regs and/or Tim-3 on CD4 effector cells. Circulating Gal9posCD4posCD25pos and Tim-3posCD4posCD25neg T cell phenotype was assessed by flow cytometry in 75 AIH patients. To evaluate whether Tim-3 expression renders CD4posCD25neg T cells amenable to T-reg control, purified CD4posCD25negTim-3pos (Tim-3pos) and CD4posCD25negTim-3neg (Tim-3neg) cells were cocultured with T-regs. To determine whether Gal9 expression is essential to function, T-regs were treated with small interfering RNA (siRNA) to repress Gal-9 translation; T-reg suppressor function was assessed by proliferation. In AIH, Tim-3pos cells within CD4posCD25neg cells and their T-betpos and RORCpos subsets were fewer and contained higher numbers of interferon-γ (IFNγ)pos and interleukin (IL)-17pos cells than healthy subjects (HS). In AIH and HS, Tim-3pos cells proliferated less vigorously and were more susceptible to T-reg control than Tim-3neg cells. In AIH, Gal9posT-regs were fewer and contained less FOXP3pos, IL-10pos, and transforming growth factor βpos and more IFNγpos and IL-17pos cells than HS. siRNA treatment of Gal-9pos T-regs drastically reduced T-reg ability to suppress CD4posCD25neg and Tim-3pos cell proliferation in AIH and HS. Tim-3pos cell percentage correlated inversely with aminotransferase and CD25negT-betpos cell values. Conclusion: Reduced levels of Tim-3 on CD4posCD25neg effector cells and of Gal9 in T-regs contribute to impaired immunoregulation in AIH by rendering effector cells less prone to T-reg control and T-regs less capable of suppressing. (HEPATOLOGY 2012)