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Ex vivo analysis of resident hepatic pro‐inflammatory CD 1d‐reactive T cells and hepatocyte surface CD 1d expression in hepatitis C
Author(s) -
Yanagisawa K.,
Yue S.,
Vliet H. J.,
Wang R.,
Alatrakchi N.,
GoldenMason L.,
Schuppan D.,
Koziel M. J.,
Rosen H. R.,
Exley M. A.
Publication year - 2013
Publication title -
journal of viral hepatitis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 100
eISSN - 1365-2893
pISSN - 1352-0504
DOI - 10.1111/jvh.12081
Subject(s) - cd1d , ex vivo , immunology , primary biliary cirrhosis , natural killer t cell , biology , chemistry , t cell , in vitro , immune system , biochemistry
Summary Hepatic CD 1d‐restricted and natural killer T ‐cell populations are heterogeneous. Classical ‘type 1′ α‐galactosylceramide‐reactive CD 1d‐restricted T cells express ‘invariant’ TCR α (‘ iNKT ’). iNKT dominating rodent liver are implicated in inflammation, including in hepatitis models. Low levels of iNKT are detected in human liver, decreased in subjects with chronic hepatitis C ( CHC ). However, high levels of human hepatic CD 161 ± CD 56 ± noninvariant pro‐inflammatory CD 1d‐restricted ‘type 2′ T cells have been identified in vitro. Unlike rodents, healthy human hepatocytes only express trace and intracellular CD 1d. Total hepatic CD 1d appears to be increased in CHC and primary biliary cirrhosis. Direct ex vivo analysis of human intrahepatic lymphocytes ( IHL ), including matched ex vivo versus in vitro expanded IHL , demonstrated detectable noninvariant CD 1d reactivity in substantial proportions of HCV ‐positive livers and significant fractions of HCV ‐negative livers. However, α‐galactosylceramide‐reactive iNKT were detected only relatively rarely. Liver CD 1d‐restricted IHL produced IFN γ, variable levels of IL ‐10 and modest levels of Th2 cytokines IL ‐4 and IL ‐13 ex vivo. In a novel FACS assay, a major fraction (10–20%) of hepatic T cells rapidly produced IFN γ and up‐regulated activation marker CD 69 in response to CD 1d. As previously only shown with murine iNKT , noninvariant human CD 1d‐specific responses were also augmented by IL ‐12. Interestingly, CD 1d was found selectively expressed on the surface of hepatocytes in CHC , but not those CHC subjects with history of alcohol usage or resolved CHC. In contrast to hepatic iNKT , noninvariant IFN γ‐producing type 2 CD 1d‐reactive NKT cells are commonly detected in CHC , together with cognate ligand CD 1d, implicating them in CHC liver damage.