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

## TL;DR

In autoimmune hepatitis, liver Treg cells are activated and functional, but there is an imbalance with CD80 and CD86 levels, which may affect immune regulation.

## Contribution

The study reveals preserved Treg frequency and function in AIH liver, but highlights an imbalance with CD80/CD86 levels and Tcon activation.

## Key findings

- Treg frequency is increased in AIH liver with an activated phenotype and high CTLA4 expression.
- CD80 and CD86 levels on B cells and monocytes are maintained or increased despite Treg presence.
- Treg transendocytosis function is preserved and enhanced by IL2 or IL10 in AIH.

## 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.

Autoimmune hepatitis (AIH) is a rare, T cell mediated liver disease that can result in acute liver and progressive chronic liver disease. We have described the phenotype of immune cells from within the liver of patients with AIH and demonstrate preserved Treg frequency with an activated phenotype and preserved functional capacity to transendocytose CD80. However, CD80 and CD86 levels were maintained suggesting an imbalance between Treg function and CD80 and CD86 availability and therefore possibly of CD28 costimulation.

Graphical Abstract