Giuseppe
Emeritus
J Immunol. 2009 Jan 15;182(2):934-47.
Endogenous 4-1BB ligand plays a critical role in protection from influenza-induced disease.
Lin GH, Sedgmen BJ, Moraes TJ, Snell LM, Topham DJ, Watts TH. - Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
A critical issue during severe respiratory infection is whether it is the virus or the host response that does the most damage.
In this study, we show that endogenous 4-1BBL plays a critical role in protecting mice from severe effects of influenza disease.
During mild respiratory influenza infection in which virus is rapidly cleared, the inducible costimulatory receptor 4-1BB is only transiently induced on lung T cells and 4-1BB ligand (4-1BBL) is completely dispensable for the initial CD8 T cell response and mouse survival.
In contrast, during more severe respiratory influenza infection with prolonged viral load, 4-1BB expression on lung CD8 T cells is sustained, and 4-1BBL-deficient mice show decreased CD8 T cell accumulation in the lungs, decreased viral clearance, impaired lung function, and increased mortality.
Transfer of an optimal number of naive Ag-specific T cells before infection protects wild-type but not 4-1BBL-deficient mice from an otherwise lethal dose of influenza virus.
Transfer of T cells lacking the proapoptotic molecule Bim extends the lifespan of 4-1BBL-deficient mice by one to three days, suggesting that at least part of the role of 4-1BB/4-1BBL is to prolong effector cell survival long enough to clear virus.
Intranasal delivery of 4-1BBL by recombinant adenovirus marginally improves survival of 4-1BBL-deficient mice at low dose, but exacerbates disease at high dose.
These findings suggest a rationale for the evolutionary accumulation of inducible costimulatory molecules, thereby allowing the immune system to sustain the expression of molecules such as 4-1BB to a level commensurate with severity of infection.
PMID: 19124736 [PubMed - in process]
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Endogenous 4-1BB ligand plays a critical role in protection from influenza-induced disease.
Lin GH, Sedgmen BJ, Moraes TJ, Snell LM, Topham DJ, Watts TH. - Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
A critical issue during severe respiratory infection is whether it is the virus or the host response that does the most damage.
In this study, we show that endogenous 4-1BBL plays a critical role in protecting mice from severe effects of influenza disease.
During mild respiratory influenza infection in which virus is rapidly cleared, the inducible costimulatory receptor 4-1BB is only transiently induced on lung T cells and 4-1BB ligand (4-1BBL) is completely dispensable for the initial CD8 T cell response and mouse survival.
In contrast, during more severe respiratory influenza infection with prolonged viral load, 4-1BB expression on lung CD8 T cells is sustained, and 4-1BBL-deficient mice show decreased CD8 T cell accumulation in the lungs, decreased viral clearance, impaired lung function, and increased mortality.
Transfer of an optimal number of naive Ag-specific T cells before infection protects wild-type but not 4-1BBL-deficient mice from an otherwise lethal dose of influenza virus.
Transfer of T cells lacking the proapoptotic molecule Bim extends the lifespan of 4-1BBL-deficient mice by one to three days, suggesting that at least part of the role of 4-1BB/4-1BBL is to prolong effector cell survival long enough to clear virus.
Intranasal delivery of 4-1BBL by recombinant adenovirus marginally improves survival of 4-1BBL-deficient mice at low dose, but exacerbates disease at high dose.
These findings suggest a rationale for the evolutionary accumulation of inducible costimulatory molecules, thereby allowing the immune system to sustain the expression of molecules such as 4-1BB to a level commensurate with severity of infection.
PMID: 19124736 [PubMed - in process]
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