The impaired immune regulation of autoimmune hepatitis is linked to a defective galectin-9/tim-3 pathway

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 imm...

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Published in:Hepatology (Baltimore, Md.) Md.), 2012-08, Vol.56 (2), p.677-686
Main Authors: Liberal, Rodrigo, Grant, Charlotte R., Holder, Beth S., Ma, Yun, Mieli-Vergani, Giorgina, Vergani, Diego, Longhi, Maria Serena
Format: Article
Language:English
Subjects:
Adolescent
Biological and medical sciences
Child
Female
Galectins - genetics
Galectins - immunology
Galectins - metabolism
Gastroenterology. Liver. Pancreas. Abdomen
Hepatitis A Virus Cellular Receptor 2
Hepatitis, Autoimmune - immunology
Hepatitis, Autoimmune - metabolism
Hepatology
Humans
Interleukin-2 Receptor alpha Subunit - metabolism
Liver - immunology
Liver - metabolism
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Lymphocytes
Male
Medical sciences
Membrane Proteins - immunology
Membrane Proteins - metabolism
Other diseases. Semiology
Recurrence
RNA, Small Interfering - genetics
Signal Transduction - immunology
T cell receptors
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - metabolism
Young Adult
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Summary: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)
ISSN:0270-9139
1527-3350
DOI:10.1002/hep.25682