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The impaired immune regulation of autoimmune hepatitis is linked to a defective galectin‐9/tim‐3 pathway
Author(s) -
Liberal Rodrigo,
Grant Charlotte R.,
Holder Beth S.,
Ma Yun,
MieliVergani Giorgina,
Vergani Diego,
Longhi Maria Serena
Publication year - 2012
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.25682
Subject(s) - il 2 receptor , immune system , biology , t cell , interleukin 21 , autoimmune hepatitis , immunology , effector , foxp3 , microbiology and biotechnology , hepatitis
In autoimmune hepatitis (AIH), liver‐damaging CD4 T cell responses are associated with defective CD4 pos CD25 pos 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 Gal9 pos CD4 pos CD25 pos and Tim‐3 pos CD4 pos CD25 neg T cell phenotype was assessed by flow cytometry in 75 AIH patients. To evaluate whether Tim‐3 expression renders CD4 pos CD25 neg T cells amenable to T‐reg control, purified CD4 pos CD25 neg Tim‐3 pos (Tim‐3 pos ) and CD4 pos CD25 neg Tim‐3 neg (Tim‐3 neg ) 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‐3 pos cells within CD4 pos CD25 neg cells and their T‐bet pos and RORC pos subsets were fewer and contained higher numbers of interferon‐γ (IFNγ) pos and interleukin (IL)‐17 pos cells than healthy subjects (HS). In AIH and HS, Tim‐3 pos cells proliferated less vigorously and were more susceptible to T‐reg control than Tim‐3 neg cells. In AIH, Gal9 pos T‐regs were fewer and contained less FOXP3 pos , IL‐10 pos , and transforming growth factor β pos and more IFNγ pos and IL‐17 pos cells than HS. siRNA treatment of Gal‐9 pos T‐regs drastically reduced T‐reg ability to suppress CD4 pos CD25 neg and Tim‐3 pos cell proliferation in AIH and HS. Tim‐3 pos cell percentage correlated inversely with aminotransferase and CD25 neg T‐bet pos cell values. Conclusion : Reduced levels of Tim‐3 on CD4 pos CD25 neg 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. (H EPATOLOGY 2012)