Ectromelia-encoded protein B22 restricts CD4+T cell activation.

Abstract Orthopoxviruses encode many immunomodulatory proteins that profoundly interfere with various aspects of the immune system. Ectromelia (ECTV) is the orthopoxvirus that naturally infects mice, affording the opportunity to study viral-host interactions that have co-evolved. Importantly, disease progression closely mimics that of monkeypox and smallpox in humans. CD4+ T cells are one immune cell type crucial for the control of ECTV and have important roles in both direct cytolytic killing of infected cells and helping B and CD8+ T cell activation. Here we show that ECTV infection of antigen presenting cells inhibits their ability to activate CD4+ T cells directly. However, the inhibitory mechanism is not straightforward as neither down-regulation of surface MHC-II nor soluble factors are responsible. A promising candidate protein for this inhibition is B22, which is located on the plasma membrane and has homologs in most virulent strains including smallpox and monkeypox, but not vaccine strains. Indeed, we have determined that B22 contributes substantially to ECTV virulence. Here we show that B22 is both necessary and sufficient to restrict CD4+ T cell activation, with experiments ongoing to elucidate the specific mechanism of inhibition.