title: IL-22-dependent attenuation of T cell-dependent (ConA) hepatitis in herpes virus entry mediator deficiency.
abstract: Coinhibitors and costimulators control intrahepatic T cell responses that trigger acute hepatitis. We used the ConA-induced hepatitis model in the mouse to test if the coinhibitor herpes virus entry mediator (HVEM) modulates hepatitis-inducing T cell responses. Compared with ConA-injected, wild-type (wt) C57BL/6 (B6) mice, HVEM-deficient (HVEM(-/-)) B6 mice showed lower serum transaminase levels and lower proinflammatory IFN-gamma, but higher protective IL-22 serum levels and an attenuated liver histopathology. The liver type I invariant NKT cell population that initiates acute hepatitis in this model was reduced in HVEM(-/-) mice but their surface phenotype was similar to that of untreated or ConA-treated wt controls. In response to mitogen injection, liver invariant NKT cells from HVEM(-/-) B6 mice produced in vivo more IL-22 but lower amounts of IFN-gamma and IL-4 than wt controls. Bone marrow chimeras showed that HVEM deficiency of the liver nonparenchymal cell population, but not of the parenchymal cell population, mediated the attenuated course of the dendritic cell- and T cell-dependent ConA hepatitis. IL-22 is produced more efficiently by liver NKT cells from HVEM(-/-) than from wt mice, and its Ab-mediated neutralization of IL-22 aggravated the course of hepatitis in wt and HVEM(-/-) mice. Hence, HVEM expression promotes pathogenic, proinflammatory Th1 responses but down-modulates protective IL-22 responses of T cells in this model of acute hepatitis.
authors.affiliation: Department of Internal Medicine I, University of Ulm, Ulm, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Wahl
authors.forename: Ursula Maria
authors.initials: UM
authors.lastname: Wegenka
authors.forename: Frank
authors.initials: F
authors.lastname: Leithäuser
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schirmbeck
authors.forename: Jörg
authors.initials: J
authors.lastname: Reimann