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The genome of cowpoxvirus (CPXV) could be considered prototypical for orthopoxviridae (OXPV) since it contains many open reading frames (ORFs) absent or lost in other OPXV, including vaccinia virus (VACV). These additional ORFs are non-essential for growth in vitro but are expected to contribute to the broad host range, virulence and immune evasion characteristics of CPXV. For instance, unlike VACV, CPXV encodes proteins that interfere with T cell stimulation, either directly or by preventing antigen presentation or co-stimulation. When studying the priming of naïve T cells, we discovered that CPXV, but not VACV, encodes a secreted factor that interferes with activation and proliferation of naïve CD8+ and CD4+ T cells, respectively, in response to anti-CD3 antibodies, but not to other stimuli. Deletion mapping revealed that the inhibitory protein is encoded by CPXV14, a small secreted glycoprotein belonging to the poxvirus immune evasion (PIE) family and containing a smallpoxvirus encoded chemokine receptor (SECRET) domain that mediates binding to chemokines. We demonstrate that CPXV14 inhibition of antibody-mediated T cell activation depends on the presence of Fc-gamma receptors (FcγRs) on bystander cells. In vitro, CPXV14 inhibits FcγR-activation by antigen/antibody complexes by binding to FcγRs with high affinity and immobilized CPXV14 can trigger signaling through FcγRs, particularly the inhibitory FcγRIIB. In vivo, CPXV14-deleted virus showed reduced viremia and virulence resulting in reduced weight loss and death compared to wildtype virus whereas both antibody and CD8+ T cell responses were increased in the absence of CPXV14. Furthermore, no impact of CPXV14-deletion on virulence was observed in mice lacking the inhibitory FcγRIIB. Taken together our results suggest that CPXV14 contributes to virulence and immune evasion by binding to host FcγRs. Author summary: Coxpoxvirus is considered the prototypical member of the closely related orthopox virus family that includes monkeypoxvirus and Variola major which caused smallpox. Presumably due to the presence of a large number of ORFs encoding for immunomodulators, CPXV is capable of infecting a wide variety of host species. Here, we show that the ORF CPXV14 encodes a small secreted protein that binds to host receptors for the constant Fc region of IgG antibodies thus preventing the ability of antibodies to engage these receptors. Viruses lacking CPXV14 are less virulent in animals but elicit increased immune responses suggesting that the interference with antibody function contributes to the ability of CPXV to evade immune control. Targeting Fc receptors is thus a new type of immune evasion mechanism that has possible applications for antibody mediated therapies. [ABSTRACT FROM AUTHOR]