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Endogenous 4-1BB ligand plays a critical role in protection from influenza-induced disease.
J Immunol. 2009 Jan 15; 182(2):934-47.JI

Abstract

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.

Authors+Show Affiliations

Department of Immunology, University of Toronto, Toronto, Ontario, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19124736

Citation

Lin, Gloria H Y., et al. "Endogenous 4-1BB Ligand Plays a Critical Role in Protection From Influenza-induced Disease." Journal of Immunology (Baltimore, Md. : 1950), vol. 182, no. 2, 2009, pp. 934-47.
Lin GH, Sedgmen BJ, Moraes TJ, et al. Endogenous 4-1BB ligand plays a critical role in protection from influenza-induced disease. J Immunol. 2009;182(2):934-47.
Lin, G. H., Sedgmen, B. J., Moraes, T. J., Snell, L. M., Topham, D. J., & Watts, T. H. (2009). Endogenous 4-1BB ligand plays a critical role in protection from influenza-induced disease. Journal of Immunology (Baltimore, Md. : 1950), 182(2), 934-47.
Lin GH, et al. Endogenous 4-1BB Ligand Plays a Critical Role in Protection From Influenza-induced Disease. J Immunol. 2009 Jan 15;182(2):934-47. PubMed PMID: 19124736.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endogenous 4-1BB ligand plays a critical role in protection from influenza-induced disease. AU - Lin,Gloria H Y, AU - Sedgmen,Bradley J, AU - Moraes,Theo J, AU - Snell,Laura M, AU - Topham,David J, AU - Watts,Tania H, PY - 2009/1/7/entrez PY - 2009/1/7/pubmed PY - 2009/2/20/medline SP - 934 EP - 47 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 182 IS - 2 N2 - 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. SN - 1550-6606 UR - https://www.unboundmedicine.com/medline/citation/19124736/Endogenous_4_1BB_ligand_plays_a_critical_role_in_protection_from_influenza_induced_disease_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=19124736 DB - PRIME DP - Unbound Medicine ER -