The oncogenic γ-herpesviruses EBV and Kaposi sarcoma–associated herpesvirus are ubiquitous human pathogens that establish lifelong latent infections maintained by intermittent viral reactivation and reinfection. Effector CD4 T cells are critical for control of viral latency and in immune therapies for virus-associated tumors. In this study, we exploited γHV68 infection of mice to enhance our understanding of the CD4 T cell response during γ-herpesvirus infection. Using a consensus prediction approach, we identified 16 new CD4 epitope-specific responses that arise during lytic infection. An additional epitope encoded by the M2 protein induced uniquely latency-associated CD4 T cells, which were not detected at the peak of lytic infection but only during latency and were not induced postinfection with a latency-deficient virus. M2-specific CD4 T cells were selectively cytotoxic, produced multiple antiviral cytokines, and sustained IL-2 production. Identification of latency-associated cytolytic CD4 T cells will aid in dissecting mechanisms of CD4 immune control of γ-herpesvirus latency and the development of therapeutic approaches to control viral reactivation and pathology.
This work was supported by National Institutes of Health (NIH) Grants F32AI084327 (to M.L.F.), T32AI049823 (to D.L.W.), CA168558 (to L.F.v.D.), and AI42927, AI082919, and CA148250 (to M.A.B.); NIH Contracts HHSN272200900042C and HHSN272200900044C (to A.S.) and HHSN272201300006C (to the NIH Tetramer Core Facility); and funds from the Trudeau Institute.
- Received August 1, 2013.
- Accepted October 8, 2014.
- Copyright © 2014 by The American Association of Immunologists, Inc.