Work

Impaired immune surveillance exposes the germinal center as a niche for gammaherpesvirus-associated B cell lymphomagenesis

Year: 2026

Type: article

Abstract: Background: Gammaherpesviruses establish lifelong latency in B cells and are linked to multiple human lymphoid malignancies, including Epstein-Barr virus (EBV)-associated lymphomas that arise at significantly increased frequency in settings of impaired immune surveillance. However, the cellular origins and evolutionary pathways of gammaherpesvirus-associated lymphomas remain incompletely defined. Methods: We used murine gammaherpesvirus 68 (MHV68) infection of β2m-deficient mice to reveal the pathological spectrum, differentiation states, and viral associations of gammaherpesvirus-driven malignancies arising under impaired immune control. Histopathologic and immunostaining analyses were used to characterize lymphoid neoplasms, B cell differentiation states, clonality, dissemination, and abundance of virus-positive cells. Results: MHV68 infection produced a broad spectrum of lymphoid neoplasms dominated by B cell lymphoproliferative diseases and B cell lymphomas. B cell lymphomas were the predominant lineage and exhibited morphologic and immunophenotypic features analogous to human EBV-associated diffuse large B cell lymphoma, follicular lymphoma, and marginal zone lymphoma. The majority displayed a germinal center B cell or post-germinal center phenotype, with 62% classified as aggressive rather than low-grade malignancies, and a subset showing clonal light chain restriction and systemic dissemination. MHV68-associated B cell lymphomas also exhibited marked heterogeneity in the abundance of virus-positive cells, including virus-rich and virus-poor tumors across multiple histologic subtypes. This pattern parallels the heterogeneity observed in EBV-associated malignancies and supports a model in which gammaherpesvirus-driven lymphomagenesis may proceed through both virus-dependent and virus-initiated pathways, including mechanisms resembling hit-and-run oncogenesis. Conclusions: These findings (a) further define the germinal center as a critical mutational niche in which gammaherpesvirus persistence and malignant transformation intersect, (b) reveal that gammaherpesvirus infection can give rise to diverse pathological outcomes even in genetically identical hosts, and (c) establish a framework for future translational studies of gammaherpesvirus-driven B cell lymphomas.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2026.1859970