ECTV-encoded protein C15 restricts CD4+ T cell activation

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 crucial for the control of ECTV, functioning as direct cytolytic effectors as well as amplifiers of both B and CD8+ T cell responses. Here we show that ECTV encoded protein C15, a member of the orthopoxvirus B22 protein family, directly inhibits CD4+ T cell activation by inhibiting MHC-II mediated peptide presentation by the infected antigen presenting cell. We provide evidence that C15 is a potent in vivo virulence factor that does not have a role in viral replication. Furthermore, we demonstrate that C15 is both necessary and sufficient to restrict CD4+ but not CD8+ T cell activation by interfering with CD4+ T cell synapse formation. Experiments are ongoing to determine the exact mechanism of action.