Journal article
Enhanced Tim3 activity improves survival after influenza infection
The Journal of immunology (1950), Vol.189(6), pp.2879-2889
09/15/2012
DOI: 10.4049/jimmunol.1102483
PMCID: PMC3436990
PMID: 22875804
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.
Details
- Title: Subtitle
- Enhanced Tim3 activity improves survival after influenza infection
- Creators
- Josalyn L Cho - Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA 02114, USAMarly I RocheBarry SandallAbraham L BrassBrian SeedRamnik J XavierBenjamin D Medoff
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.189(6), pp.2879-2889
- DOI
- 10.4049/jimmunol.1102483
- PMID
- 22875804
- PMCID
- PMC3436990
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Grant note
- R01 HL088297 / NHLBI NIH HHS T32 HL007874 / NHLBI NIH HHS T32 HL07874 / NHLBI NIH HHS F32 HL099070 / NHLBI NIH HHS R01 AI091786 / NIAID NIH HHS P30 DK043351 / NIDDK NIH HHS
- Language
- English
- Date published
- 09/15/2012
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; Internal Medicine
- Record Identifier
- 9984094326802771
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