HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement A correction has been published Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lin, G. H. Y. Articles by Watts, T. H. Search for Related Content PubMed PubMed Citation Articles by Lin, G. H. Y. Articles by Watts, T. H.

Endogenous 4-1BB Ligand Plays a Critical Role in Protection from Influenza-Induced Disease¹

Gloria H. Y. Lin^*, Bradley J. Sedgmen^2,*, Theo J. Moraes^*, Laura M. Snell^*, David J. Topham and Tania H. Watts^3,*

^* Department of Immunology, University of Toronto, Toronto, Ontario, Canada; and David H. Smith Center for Vaccine Biology and Immunology, University of Rochester Medical Center, Rochester, NY 14642

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants MOP 84419 and PAN 83156 from the Canadian Institutes of Health Research (CIHR) (to T.H.W.). G.H.Y.L. was funded by a CIHR Canada graduate scholarship award and an Ontario Graduate scholarship. T.J.M. is funded by a CIHR Canadian Child Health Clinician Scientist training award, and L.M.S. is funded by a scholarship from the Fonds de la Recherche en Santé du Québec.

² Current address: CSL Limited, A.C.N. 051 588 348, 45 Poplar Road, Parkville, Victoria 3052, Australia.

³ Address correspondence and reprint requests to Dr. Tania Watts, University of Toronto, Department of Immunology, 1 King’s College Circle, Toronto, Ontario M5S 1A8, Canada. E-mail address: tania.watts{at}utoronto.ca

⁴ Abbreviations used in this paper: 4-1BBL, 4-1BB ligand; FMO, fluorescence minus one; HAU, hemagglutinating units; i.n., intranasal; AdV, adenovirus 5; MLN, mediastinal lymph node; WT, wild type.

⁵ The online version of this article contains supplemental material.