The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20071135
The Journal of Experimental Medicine, Vol. 205, No. 3, 669-684
The Rockefeller University Press, 0022-1007 $30.00
© Evans et al.
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ARTICLE

 A gammaherpesvirus-secreted activator of Vβ4+ CD8+ T cells regulates chronic infection and immunopathology

Andrew G. Evans1,2, Janice M. Moser1,2, Laurie T. Krug1,2, Veranika Pozharskaya3, Ana L. Mora4, and Samuel H. Speck1,2

1 Emory Vaccine Center, 2 Department of Microbiology and Immunology, 3 Department of Pediatrics, and 4 Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322

CORRESPONDENCE Samuel H. Speck: sspeck{at}emory.edu

Little is known about herpesvirus modulation of T cell activation in latently infected individuals or the implications of such for chronic immune disorders. Murine gammaherpesvirus 68 (MHV68) elicits persistent activation of CD8+ T cells bearing a Vβ4+ T cell receptor (TCR) by a completely unknown mechanism. We show that a novel MHV68 protein encoded by the M1 gene is responsible for Vβ4+ CD8+ T cell stimulation in a manner reminiscent of a viral superantigen. During infection, M1 expression induces a Vβ4+ effector T cell response that resists functional exhaustion and appears to suppress virus reactivation from peritoneal cells by means of long-term interferon-{gamma} (IFN{gamma}) production. Mice lacking an IFN{gamma} receptor (IFN{gamma}R–/–) fail to control MHV68 replication, and Vβ4+ and CD8+ T cell activation by M1 instead contributes to severe inflammation and multiorgan fibrotic disease. Thus, M1 manipulates the host CD8+ T cell response in a manner that facilitates latent infection in an immunocompetent setting, but promotes disease during a dysregulated immune response. Identification of a viral pathogenecity determinant with superantigen-like activity for CD8+ T cells broadens the known repertoire of viral immunomodulatory molecules, and its function illustrates the delicate balance achieved between persistent viruses and the host immune response.

Abbreviations used: BAC, bacterial artificial chromosome; ICC, intracellular cytokine; IM, infectious mononucleosis; MEF, mouse embryonic fibroblast; ORF, open reading frame; PEC, peritoneal exudate cell; SAP, SLAM-associated protein.

J.M. Moser's present address is VaxDesign Corporation, Orlando, FL 32826.


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