title: CD161(+)CD4(+) T cells are enriched in the liver during chronic hepatitis and associated with co-secretion of IL-22 and IFN-γ.
abstract: 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 enrichment of 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 result 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.
authors.affiliation: Peter Medawar Building for Pathogen Research Oxford, UK.
authors.forename: Yu-Hoi
authors.initials: YH
authors.lastname: Kang
authors.forename: Bianca
authors.initials: B
authors.lastname: Seigel
authors.forename: Bertram
authors.initials: B
authors.lastname: Bengsch
authors.forename: Vicki M
authors.initials: VM
authors.lastname: Fleming
authors.forename: Eva
authors.initials: E
authors.lastname: Billerbeck
authors.forename: Ruth
authors.initials: R
authors.lastname: Simmons
authors.forename: Lucy
authors.initials: L
authors.lastname: Walker
authors.forename: Chris B
authors.initials: CB
authors.lastname: Willberg
authors.forename: Eleanor J
authors.initials: EJ
authors.lastname: Barnes
authors.forename: Anisha
authors.initials: A
authors.lastname: Bhagwanani
authors.forename: Ye H
authors.initials: YH
authors.lastname: Oo
authors.forename: Hubert E
authors.initials: HE
authors.lastname: Blum
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman