A gammaherpesvirus-secreted activator of Vbeta4+ CD8+ T cells regulates chronic infection and immunopathology.
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 Vbeta4(+) T cell receptor (TCR) by a completely unknown mechanism. We show that a novel MHV68 protein encoded by the M1 gene is responsible for Vbeta4(+) CD8(+) T cell stimulation in a manner reminiscent of a viral superantigen. During infection, M1 expression induces a Vbeta4(+) effector T cell response that resists functional exhaustion and appears to suppress virus reactivation from peritoneal cells by means of long-term interferon-gamma (IFNgamma) production. Mice lacking an IFNgamma receptor (IFNgammaR(-/-)) fail to control MHV68 replication, and Vbeta4(+) 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.
Evans
Andrew G
AG
Emory Vaccine Center, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Moser
Janice M
JM
Krug
Laurie T
LT
Pozharskaya
Veranika
V
Mora
Ana L
AL
Speck
Samuel H
SH
D000818:Animals; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000145:classification / Q000276:immunology*; D002908:Chronic Disease; D018142:Gammaherpesvirinae / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D006566:Herpesviridae Infections / Q000276:immunology* / Q000473:pathology*; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D010641:Phenotype; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology; D000096743:Interferon gamma Receptor
D007371:Interferon-gamma; D016693:Receptors, Antigen, T-Cell, alpha-beta; D017471:Receptors, Interferon; D014764:Viral Proteins; D000096743:Interferon gamma Receptor