Conditional T and NK cell antagonism by a giant and highly conserved orthopoxvirus virulence factor

Orthopoxviruses, including variola and monkeypox, have long ravaged human populations for reasons that remain unclear. Members of the highly conserved B22 protein family are notable for their extreme virulence via targeting of multiple host defenses. C15, the B22 protein of ectromelia (murine model for smallpox), is known to target NK cells and CD4+ T cells, and, as shown here, also CD8+ T cells. Unexpectedly, in C57Bl/6 mice, T cell responses were larger, more functional, and phenotypically enhanced in the face of C15 expression. cDC1-mediated cross-presentation contributed to enhanced CD8+ T cell responses, but the primary contributor was C15-mediated antagonism of NK cell-dependent viral control, and single cell analysis identified a potential signaling scaffold downstream of C15 inhibitory activity. Conversely, in BALB/c mice, which mount suboptimal NK cell responses, T cells were more prominently inhibited. These studies introduce the concept of conditional immunomodulation dictated by the immunocompetence profile of the host.