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CD8⁺ T Cell Dysfunction and Increase in Murine Gammaherpesvirus Latent Viral Burden in the Absence of 4-1BB Ligand¹

Shinichiro Fuse^*, Sarah Bellfy^*, Hideo Yagita and Edward J. Usherwood^2,*

^* Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756; and Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

Studies of costimulatory receptors belonging to the TNFR family have revealed their diverse roles in affecting different stages of the T cell response. The 4-1BB ligand (4-1BBL)/4-1BB pathway has emerged as a receptor-ligand pair that impacts not the initial priming, but later phases of the T cell response, such as sustaining clonal expansion and survival, maintaining memory CD8⁺ T cells, and supporting secondary expansion upon Ag challenge. Although the role of this costimulatory pathway in CD8⁺ T cell responses to acute viral infections has been well-studied, its role in controlling chronic viral infections in vivo is not known to date. Using the murine gammaherpesvirus-68 (MHV-68) model, we show that 4-1BBL-deficient mice lack control of MHV-68 during latency and show significantly increased latent viral loads. In contrast to acute influenza infection, the numbers of MHV-68-specific memory CD8⁺ T cells were maintained during latency. However, the virus-specific CD8⁺ T cells showed defects in function, including decreased cytolytic function and impaired secondary expansion. Thus, 4-1BBL deficiency significantly affects the function, but not the number, of virus-specific CD8⁺ T cells during gammaherpesvirus latency, and its absence results in an increased viral burden. Our study suggests that the 4-1BB costimulatory pathway plays an important role in controlling chronic viral 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 National Institutes of Health Grant CA103642.

² Address correspondence and reprint requests to Dr. Edward J. Usherwood, Department of Microbiology and Immunology, Dartmouth Medical School, 1 Medical Center Drive, Lebanon, NH 03756. E-mail address: edward.j.usherwood{at}dartmouth.edu

³ Abbreviations used in this paper: 4-1BBL, 4-1BB ligand; DC, dendritic cell; BM-MC, bone marrow-derived mast cell; LCMV, lymphocytic choriomeningitis virus; MHV-68, murine gammaherpesvirus-68; i.n., intranasal; QF, quantitative fluorescent; CMC, carboxymethyl-cellulose; CTO, CellTracker Orange; MLN, mesenteric lymph node; VSV, vesicular stomatitis virus.

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