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CD8 T Cells Utilize TRAIL to Control Influenza Virus Infection¹

Erik L. Brincks^*,, Arna Katewa, Tamara A. Kucaba, Thomas S. Griffith^*, and Kevin L. Legge^2,*,

^* Interdisciplinary Graduate Program in Immunology, Department of Urology, and Department of Pathology, University of Iowa, Iowa City, IA 52242

Elimination of influenza virus-infected cells during primary influenza virus infections is thought to be mediated by CD8⁺ T cells though perforin- and FasL-mediated mechanisms. However, recent studies suggest that CD8⁺ T cells can also utilize TRAIL to kill virally infected cells. Therefore, we herein examined the importance of TRAIL to influenza-specific CD8⁺ T cell immunity and to the control of influenza virus infections. Our results show that TRAIL deficiency increases influenza-associated morbidity and influenza virus titers, and that these changes in disease severity are coupled to decreased influenza-specific CD8⁺ T cell cytotoxicity in TRAIL^–/– mice, a decrease that occurs despite equivalent numbers of pulmonary influenza-specific CD8⁺ T cells. Furthermore, TRAIL expression occurs selectively on influenza-specific CD8⁺ T cells, and high TRAIL receptor (DR5) expression occurs selectively on influenza virus-infected pulmonary epithelial cells. Finally, we show that adoptive transfer of TRAIL^+/+ but not TRAIL^–/– CD8⁺ effector T cells alters the mortality associated with lethal dose influenza virus infections. Collectively, our results suggest that TRAIL is an important component of immunity to influenza infections and that TRAIL deficiency decreases CD8⁺ T cell-mediated cytotoxicity, leading to more severe influenza infections.

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 a University of Iowa Carver College of Medicine Collaborative Pilot Grant (to T.S.G. and K.L.L.) and a National Institutes of Health Award (R21 AI072032; to K.L.L.). E.L.B. is supported by an American Heart Association Predoctoral Fellowship.

² Address correspondence and reprint requests to Dr. Kevin L. Legge, Department of Pathology (1036ML), University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242. E-mail address: kevin-legge{at}uiowa.edu

³ Abbreviations used in this paper: p.i., postinfection; DR5, death receptor 5 or TRAIL receptor 2; EIU, egg infectious units; i.n., intranasally; MFI, mean fluorescence intensity; NP, nucleocapsid protein; PA, acid polymerase; TCID₅₀, 50% tissue culture-infective dose.

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