CD4 T cells specific for a latency-associated γ-herpesvirus epitope are polyfunctional and cytotoxic.
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.
Trudeau Institute, Saranac Lake, NY 12983;
Michael L
ML
Freeman
Trudeau Institute, Saranac Lake, NY 12983;
Claire E
CE
Burkum
Trudeau Institute, Saranac Lake, NY 12983;
Tres
T
Cookenham
Trudeau Institute, Saranac Lake, NY 12983;
Alan D
AD
Roberts
Trudeau Institute, Saranac Lake, NY 12983;
Kathleen G
KG
Lanzer
Trudeau Institute, Saranac Lake, NY 12983;
Gail E
GE
Huston
Trudeau Institute, Saranac Lake, NY 12983;
Meghan K
MK
Jensen
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
John
J
Sidney
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
Bjoern
B
Peters
Trudeau Institute, Saranac Lake, NY 12983;
Jacob E
JE
Kohlmeier
Trudeau Institute, Saranac Lake, NY 12983;
David L
DL
Woodland
Department of Microbiology, University of Colorado School of Medicine, Aurora, CO 80045; and Department of Immunology, University of Colorado School of Medicine, Aurora, CO 80045.
Linda F
LF
van Dyk
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
Alessandro
A
Sette
Trudeau Institute, Saranac Lake, NY 12983; mblackman@trudeauinstitute.org.
Marcia A
MA
Blackman
D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D018142:Gammaherpesvirinae / Q000276:immunology*; D006566:Herpesviridae Infections / Q000276:immunology / Q000821:virology; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D017735:Virus Latency
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D010455:Peptides; D007371:Interferon-gamma