IL-22 promotes the establishment of chronic gammaherpesvirus infection by supporting the germinal center response
- 1Department of Investigative Medicine and Center for Immunobiology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, Michigan, United States of America
Abstract
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. Author summary: Gammaherpesviruses are double-stranded DNA viruses that establish lifelong infections in over 95% of adults worldwide and are associated with multiple cancers and autoimmune disease. To persist within the host, these viruses exploit germinal center B cells to establish a long-lived latent reservoir. Although the cytokine IL-22 is best known for its protective role in bacterial and fungal infections, its contribution to gammaherpesvirus infection was unknown. Using a murine model of gammaherpesvirus infection, we demonstrate that IL-22 promotes the establishment of chronic gammaherpesvirus infection without affecting acute viral replication. Mice lacking IL-22 exhibited reduced latent viral burden accompanied by impaired germinal center and plasma-cell responses along with diminished virus-specific and polyclonal antibody production. These findings suggest that IL-22 helps create an immune environment that favors viral latency. Our work identifies a previously unrecognized role for IL-22 in supporting chronic gammaherpesvirus infection and provides new insights into how host immune pathways contribute to lifelong gammaherpesvirus infection.
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BibTeX
@article{majeed2026il22,
title = {{IL-22 promotes the establishment of chronic gammaherpesvirus infection by supporting the germinal center response}},
author = {Sheikh Tahir Majeed and Samantha M. Bradford and Christopher N. Jondle},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1014016},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014016},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - IL-22 promotes the establishment of chronic gammaherpesvirus infection by supporting the germinal center response
AU - Sheikh Tahir Majeed
AU - Samantha M. Bradford
AU - Christopher N. Jondle
PY - 2026
DA - 2026/09/08
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014016
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014016
AB - 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. Author summary: Gammaherpesviruses are double-stranded DNA viruses that establish lifelong infections in over 95% of adults worldwide and are associated with multiple cancers and autoimmune disease. To persist within the host, these viruses exploit germinal center B cells to establish a long-lived latent reservoir. Although the cytokine IL-22 is best known for its protective role in bacterial and fungal infections, its contribution to gammaherpesvirus infection was unknown. Using a murine model of gammaherpesvirus infection, we demonstrate that IL-22 promotes the establishment of chronic gammaherpesvirus infection without affecting acute viral replication. Mice lacking IL-22 exhibited reduced latent viral burden accompanied by impaired germinal center and plasma-cell responses along with diminished virus-specific and polyclonal antibody production. These findings suggest that IL-22 helps create an immune environment that favors viral latency. Our work identifies a previously unrecognized role for IL-22 in supporting chronic gammaherpesvirus infection and provides new insights into how host immune pathways contribute to lifelong gammaherpesvirus infection.
SN - 1553-7374
ER -