Non-classical major histocompatibility factor H2-O counteracts gammaherpesvirus manipulation of the germinal center response

Abstract

Abstract Gammaherpesviruses, such as Epstein Barr virus, infect 95% of adults and form lifelong infection primarily through manipulation of B cells. During primary infection, gammaherpesviruses establish latent infections within B cells and drive robust, polyclonal germinal center (GC) responses, which atypically include B cells specific to both viral and self antigens. Consequently, this humoral response results in production of both autoantibodies, and interestingly, antibodies reactive to antigens of non-human species. While this non-physiological production of antibodies suggests viral manipulation of immune tolerance, the underlying mechanisms driving these phenomena are poorly understood. Utilizing murine gammaherpesvirus 68 (MHV68), a rodent pathogen highly similar to EBV which serves as an animal model of EBV infection, we have discovered that the host factor H2-O (HLA-DO in humans) attenuates MHV68 latency establishment and the MHV68 driven GC response. H2-O acts as an inhibitor of H2-M (HLA-DM), the protein which regulates peptide exchange and thus the repertoire of peptides associated with the MHC-II peptide binding groove. We found that mice deficient in H2-O displayed increased MHV68 latent reservoirs, increased GC response, and a selective increase in dsDNA specific IgG, with no change in virus specific IgG at the peak of latent viral infection. These results show a novel role of H2-O in attenuating the non-physiological, self-directed B cell response driven by MHV68. Furthermore, these studies are the first to demonstrate that fine tuning of MHC-II antigen presentation is sufficient to alter the self-directed B cell differentiation usurped by a ubiquitous viral pathogen during establishment of life-long infection.