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J Immunol. 2012 Sep 15;189(6):2879-89. doi: 10.4049/jimmunol.1102483. Epub 2012 Aug 8.

Enhanced Tim3 activity improves survival after influenza infection.

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  • 1Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA 02114, USA.

Abstract

Influenza is a major cause of morbidity and mortality in the United States. Studies have shown that excessive T cell activity can mediate pneumonitis in the setting of influenza infection, and data from the 2009 H1N1 pandemic indicate that critical illness and respiratory failure postinfection were associated with greater infiltration of the lungs with CD8+ T cells. T cell Ig and mucin domain 3 (Tim3) is a negative regulator of Th1/Tc1-type immune responses. Activation of Tim3 on effector T cells has been shown to downregulate proliferation, cell-mediated cytotoxicity, and IFN-γ production, as well as induce apoptosis. In this article, we demonstrate that deletion of the terminal cytoplasmic domain of the Tim3 gene potentiates its ability to downregulate Tc1 inflammation, and that this enhanced Tim3 activity is associated with decreased phosphorylation of the TCR-CD3ζ-chain. We then show that mice with this Tim3 mutation infected with influenza are protected from morbidity and mortality without impairment in viral clearance or functional heterotypic immunity. This protection is associated with decreased CD8+ T cell proliferation and decreased production of inflammatory cytokines, including IFN-γ. Furthermore, the Tim3 mutation was protective against mortality in a CD8+ T cell-specific model of pneumonitis. These data suggest that Tim3 could be targeted to prevent immunopathology during influenza infection and demonstrate a potentially novel signaling mechanism used by Tim3 to downregulate the Tc1 response.

PMID:
22875804
[PubMed - indexed for MEDLINE]
PMCID:
PMC3436990
Free PMC Article

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