The inhibition of NK cell-mediated control by the ectromelia virulence factor C15 enhances the magnitude and functionality of CD4+ and CD8+ T cell responses to infection 4522

Abstract Description Orthopoxviruses, such as variola and Mpox, encode a myriad of immunomodulatory proteins to promote pathogenesis. One notable family is the B22 family of proteins, which are highly conserved surface glycoproteins that potently inhibit T cell activation in vitro and ex vivo. Previously, we determined that the ectromelia virus (ECTV) B22 protein, C15, also facilitates early viral replication in C57BL/6 mice through the targeting of NK cell-mediated control of viral dissemination. As a result, in vivo ECTV replication is significantly restricted in the absence of C15. The impact of this early restriction event on the generation of anti-ECTV T cell responses remains unknown. We hypothesized that ECTVΔC15 would induce more robust and polyfunctional T cell responses to infection compared to WT ECTV. However, we found that ECTVΔC15 infection induced significantly weaker CD4+ and CD8+ T cell responses. Specifically, following ECTVΔC15 infection, 1) there were less antigen-specific cytotoxic CD4+ T cells, 2) effector CD8+ T cells exhibited markedly less activation marker expression (e.g., CD25 and CD69), and 3) effector CD8+ T cells developed markers of terminal differentiation (i.e., CX3CR1) earlier during infection. Overall, we conclude that the early restriction of viral replication in the absence of C15 stunts the development of the anti-ECTV T cell response. Future work seeks to explore how this early restriction impacts long-term memory and protection from orthologous challenge. Funding Sources Supported by NIH/NIAID 1R01AI182049-01; 1F31AI183694-01. Topic Categories Viral Immunology (VIR)