A novel wild-derived MHC-linked locus regulates host immunity to gammaherpesvirus infection

Waytashek, C. M.; Nelson, E. A.; Sessions, K. J.; Dalhberg, K.; Fondakowski, M.; Bubier, J.; Usherwood, E. J.; Krementsov, D. N.

doi:10.64898/2026.06.23.733957

bioRxiv · 10.64898/2026.06.23.733957

A novel wild-derived MHC-linked locus regulates host immunity to gammaherpesvirus infection

Waytashek, C. M.·Nelson, E. A.·Sessions, K. J.·Dalhberg, K.·Fondakowski, M.·Bubier, J.·Usherwood, E. J.·Krementsov, D. N.

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Abstract

Inefficient host control of infection by gammaherpesviruses is a risk factor for lymphoproliferative disease, autoimmunity, and cancer, yet naturally occurring genetic determinants of viral control remain poorly defined. Previously, we discovered that wild-derived PWD/PhJ (PWD) mice exhibit markedly improved control of murine gammaherpesvirus 68 (MHV-68) replication compared with C57BL/6J (B6) mice. This elite control of viral replication was linked to muted T cell responses, but partially dependent on NK cells. Here, we used genetic approaches to identify host determinants controlling MHV-68 resistance in PWD mice. Analysis of B6PWDF1 and B6PWDF2 populations suggested the existence of a major locus in the PWD genome contributing to MHV-68 resistance. Using B6.ChrPWD chromosome substitution (consomic) mice, we mapped a major resistance locus to Chr 17 and refined the required interval to 27.6-49.4 Mb, including the MHC locus. While B6.Chr17PWD mice recapitulated muted T cell responses observed in PWD mice, they controlled viral burden independent of NK cells and without reduced frequencies of infected germinal center B cells, indicating that resistance of PWD mice comprises multiple genetically and mechanistically distinct pathways. While the NK cell receptor complex on PWD chromosome 6 did not provide protection, genotype-phenotype analysis of the B6PWDF2 cohort revealed additional non-Chr 17-linked loci contributing to viral control. Together, our results identify a novel MHC-linked locus regulating gammaherpesvirus burden with minimal cytotoxic T cell expansion, demonstrating that effective host control of gammaherpesviruses can be achieved by diverse immune mechanisms. ImportancePoor host control of human gammaherpesvirus infection is linked to cancer and autoimmunity, but how natural genetic variation impacts immune mechanism of control is poorly defined. In this study, we examined genetic mechanisms linked to superior control of gammaherpesvirus infection. We identified a novel MHC-linked locus that regulates gammaherpesvirus burden without a large expansion of cytotoxic T cells and independent of NK cells. These findings show that host control of gammaherpesviruses can be achieved through diverse immune mechanisms that are driven by variation in host genetic background.

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Waytashek, C. M., Nelson, E. A., Sessions, K. J., Dalhberg, K., Fondakowski, M., Bubier, J., Usherwood, E. J., Krementsov, D. N.. 2026-06-28. A novel wild-derived MHC-linked locus regulates host immunity to gammaherpesvirus infection. https://doi.org/10.64898/2026.06.23.733957

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