An imbalance between CD80 and CD86 levels and CD4 regulatory T cell number and transendocytosis function exists in the liver in autoimmune hepatitis

Abstract

Impairment in Regulatory CD4 T cells (Treg) number and function have been implicated in autoimmune hepatitis (AIH). Treg are critical regulators of CD28 costimulation through CTLA4-mediated CD80 and CD86 control. We sought evidence for hepatic Treg frequency, phenotype, and function, and CD80/CD86 availability in AIH. Hepatic immune cells were isolated from eight patients with AIH and compared with cirrhotic and non-cirrhotic controls. Cells were assessed by flow cytometry and function was assessed by acquisition of CD80 from model antigen-presenting cells (APCs). We observed that Treg frequency was increased in AIH liver. Treg had an activated phenotype with a high CTLA4 expression and higher frequency of CTLA4 + PD1+ cells compared to non-AIH. Conventional CD4 T cells (Tcon) had an activated phenotype with increased HLA-DR expression, despite patients being in biochemical and histological remission. CD80 and CD86 expressions on B cells and monocytes were maintained or increased despite the excess of Treg, suggesting an imbalance between Treg and CD28 ligand availability. Hepatic Treg in AIH had preserved function for transendocytosis of CD80, which was enhanced by IL2 or IL10, demonstrating capacity for CD28 control. Overall, hepatic Treg have an activated phenotype and we did not observe reduced frequency or transendocytosis function of Treg in cirrhotic liver or (sub)acute liver failure from AIH. However, there is an imbalance between Treg function and CD80 and CD86 availability, with Tcon activation. This suggests that advanced AIH is not associated with reduced Treg frequency or function in the liver, but with an excess of CD80 and CD86.

Keywords: CD28 costimulation; CD80; CD86; Treg; autoimmune hepatitis; transendocytosis.