CD161⁺CD4⁺ T cells are enriched in the liver during chronic hepatitis and associated with co-secretion of IL-22 and IFN-_γ

Hepatitis C virus infection is a major cause of chronic liver disease. CD4⁺ T cells play a key role in disease outcome. However, the critical functions and associated phenotypes of intrahepatic CD4⁺ T cells are not well defined. We have previously shown that CD8⁺T cells expressing the C type lectin CD161 are highly enriched in the human liver, especially during chronic hepatitis. These cells are associated with a type 17 differentiation pattern and express cytokines including IL-17A, IL-22, and IFN-_γ. We therefore analyzed expression of CD161 on CD4⁺ T cells in blood and liver and addressed the relevant phenotype and functional capacity of these populations. We observed marked enrichmentof CD161⁺ CD4⁺ T cells in the liver during chronic hepatitis such that they are the dominant subtype (mean 55% of CD4⁺ T cells). IL-22 and IL-17 secreting CD4⁺ T cells were readily found in the livers of HCV and NASH donors, although not enriched compared to blood. There was, however, specific enrichment of a novel subset of IL-22/IFN-_γ dual secretors (p = 0.02) compared to blood, a res+ult reconfirmed with direct ex vivo analyses. These data indicate the dominance of CD161⁺ expressing lymphocyte populations within the hepatic infiltrate, associated with a distinct cytokine profile. Given their documented roles as antiviral and hepatoprotective cytokines respectively, the impact of co-secretion of IFN-_γ and IL-22 in the liver may be particularly significant.