title: Clonal exhaustion as a mechanism to protect against severe immunopathology and death from an overwhelming CD8 T cell response.
abstract: The balance between protective immunity and immunopathology often determines the fate of the virus-infected host. How rapidly virus is cleared is a function of initial viral load, viral replication rate, and efficiency of the immune response. Here, we demonstrate, with three different inocula of lymphocytic choriomeningitis virus (LCMV), how the race between virus replication and T cell responses can result in different disease outcomes. A low dose of LCMV generated efficient CD8 T effector cells, which cleared the virus with minimal lung and liver pathology. A high dose of LCMV resulted in clonal exhaustion of T cell responses, viral persistence, and little immunopathology. An intermediate dose only partially exhausted the T cell responses and resulted in significant mortality, and the surviving mice developed viral persistence and massive immunopathology, including necrosis of the lungs and liver. This suggests that for non-cytopathic viruses like LCMV, hepatitis C virus, and hepatitis B virus, clonal exhaustion may be a protective mechanism preventing severe immunopathology and death.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School , Hannover , Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Cornberg
authors.affiliation: Program in Immunology and Virology, Department of Pathology, University of Massachusetts Medical School , Worcester, MA , USA.
authors.forename: Laurie L
authors.initials: LL
authors.lastname: Kenney
authors.affiliation: Program in Immunology and Virology, Department of Pathology, University of Massachusetts Medical School , Worcester, MA , USA.
authors.forename: Alex T
authors.initials: AT
authors.lastname: Chen
authors.affiliation: Program in Immunology and Virology, Department of Pathology, University of Massachusetts Medical School , Worcester, MA , USA.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Waggoner
authors.affiliation: Program in Immunology and Virology, Department of Pathology, University of Massachusetts Medical School , Worcester, MA , USA.
authors.forename: Sung-Kwon
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna , Vienna , Austria.
authors.forename: Hans P
authors.initials: HP
authors.lastname: Dienes
authors.affiliation: Program in Immunology and Virology, Department of Pathology, University of Massachusetts Medical School , Worcester, MA , USA.
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Welsh
authors.affiliation: Program in Immunology and Virology, Department of Pathology, University of Massachusetts Medical School , Worcester, MA , USA.
authors.forename: Liisa K
authors.initials: LK
authors.lastname: Selin
keywords: CD8; LCMV; T cells; clonal exhaustion; immunopathology; liver; lung