IL-22 Promotes Gammaherpesvirus Latency and Pathogenesis by Supporting Germinal Center Expansion and Polyclonal Autoimmunity

Abstract

Gammaherpesviruses, including human Epstein-Barr Virus (EBV) and Kaposis Sarcoma-associated Herpesvirus (KSHV), are ubiquitous oncogenic pathogens linked to diverse malignancies, including Burkitt lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma, as well as Kaposis sarcoma, as well as autoimmune disorders, most notably Multiple Sclerosis. These viruses colonize naive B cells and drive a robust, polyclonal germinal center response to expand the latent viral reservoir and establish lifelong infection in memory B cells. Despite the clinical burden of these viruses, the host factors they usurp to maintain this chronic state remain poorly defined. Interleukin-22 (IL-22) is a critical cytokine traditionally recognized for its protective roles in bacterial and fungal defense; however, its involvement in gammaherpesvirus pathogenesis has not been previously explored. Using murine gammaherpesvirus 68 (MHV68) as a tractable in vivo model, we identify IL-22 as a novel proviral factor that promotes the establishment and maintenance of chronic infection. We show that MHV68 infection triggers a robust, T-cell-driven IL-22 response across primary and secondary sites of infection. Our studies in IL-22-/- mice reveal a profound reduction in the virus-driven germinal center response, leading to diminished viral latency and impaired reactivation competency. Furthermore, we demonstrate that IL-22 supports the induction of the polyclonal, "irrelevant" antibody response, a signature of gammaherpesvirus-induced immunopathology. Together, our data reveal that gammaherpesviruses exploit the IL-22 axis to establish a supportive environment within the host, positioning this cytokine as a potential therapeutic target for disrupting the establishment of lifelong viral latency and its associated diseases. Author SummaryGammaherpesviruses are oncogenic double-stranded DNA viruses that establish lifelong infections in over 95% of adults worldwide and are multiple cancers, including many B-cell lymphomas. While the cytokine IL-22 is known for its role in clearing bacterial and fungal infections, its influence on chronic viral infections is poorly understood. In this study, we demonstrate for the first time that IL-22 plays a critical proviral role during gammaherpesvirus infection. By utilizing a murine model, we show that loss of IL-22 suppresses the establishment of viral latency, reduces viral reactivation and dampens the virus-driven germinal center response. viral latency and reactivation. Furthermore, we find that IL-22 signaling supports non-specific, polyclonal antibody surge characteristic of these infections. Our findings suggest that the virus exploits the IL-22 axis to shape a supportive microenvironment for its reservoir, identifying this pathway as a potential therapeutic target to limit viral latency and its associated immunopathology.