IL-22 promotes the establishment of chronic gammaherpesvirus infection by supporting the germinal center response.

Gammaherpesviruses, including human Epstein-Barr Virus (EBV) and Kaposi's Sarcoma-associated Herpesvirus (KSHV), establish lifelong latent infections that contribute to multiple cancers and Multiple Sclerosis. These viruses colonize naïve 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 that support chronic infection 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 explored. Using murine gammaherpesvirus 68 (MHV68) as a tractable in vivo model, we identify IL-22 as a host factor that promotes the establishment of chronic gammaherpesvirus infection. MHV68 infection triggers robust IL-22 production across multiple anatomical sites and immune cell populations. Although IL-22 deficiency did not affect acute viral replication, IL-22-/- mice exhibited a sustained reduction in latent viral burden within both the spleen and peritoneal cavity. This phenotype was accompanied by impaired germinal center B cell and T follicular helper cell responses, reduced plasma-cell expansion, diminished virus-specific antibody responses, and attenuated polyclonal autoreactive antibody production. Furthermore, IL-22 deficiency was associated with reduced systemic BAFF levels, suggesting that IL-22 contributes to the establishment of a germinal center microenvironment that supports chronic infection. Together, these findings identify IL-22 as a previously unrecognized regulator of chronic gammaherpesvirus infection and reveal a role for this cytokine in coordinating germinal center responses, humoral immunity, and latent reservoir establishment, providing new insight into how host immune pathways contribute to lifelong gammaherpesvirus infection.