CD200 receptor restriction of myeloid cell responses antagonizes antiviral immunity and facilitates cytomegalovirus persistence within mucosal tissue.
CD200 receptor restriction of myeloid cell responses antagonizes antiviral immunity and facilitates cytomegalovirus persistence within mucosal tissue.
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DOI：
10.1371/journal.ppat.1004641
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发表时间：
2015-02
期刊：
影响因子：
6.7
通讯作者：
Humphreys IR
中科院分区：
文献类型：
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作者：
Stack G;Jones E;Marsden M;Stacey MA;Snelgrove RJ;Lacaze P;Jacques LC;Cuff SM;Stanton RJ;Gallimore AM;Hussell T;Wilkinson GW;Ghazal P;Taylor PR;Humphreys IR
CD200 receptor (CD200R) negatively regulates peripheral and mucosal innate immune responses. Viruses, including herpesviruses, have acquired functional CD200 orthologs, implying that viral exploitation of this pathway is evolutionary advantageous. However, the role that CD200R signaling plays during herpesvirus infection in vivo requires clarification. Utilizing the murine cytomegalovirus (MCMV) model, we demonstrate that CD200R facilitates virus persistence within mucosal tissue. Specifically, MCMV infection of CD200R-deficient mice (CD200R-/-) elicited heightened mucosal virus-specific CD4 T cell responses that restricted virus persistence in the salivary glands. CD200R did not directly inhibit lymphocyte effector function. Instead, CD200R-/- mice exhibited enhanced APC accumulation that in the mucosa was a consequence of elevated cellular proliferation. Although MCMV does not encode an obvious CD200 homolog, productive replication in macrophages induced expression of cellular CD200. CD200 from hematopoietic and non-hematopoietic cells contributed independently to suppression of antiviral control in vivo. These results highlight the CD200-CD200R pathway as an important regulator of antiviral immunity during cytomegalovirus infection that is exploited by MCMV to establish chronicity within mucosal tissue. Immune inhibitory receptors, including CD200 receptor (CD200R), can limit immune responses in the mucosa to restrict reactivity to the plethora of harmless antigens that mucosal surfaces are continually exposed to. However, viruses may exploit these suppressive mechanisms to enable their persistence and spread. Many viruses, including herpesviruses, have acquired functional homologs of CD200, the ligand of CD200R, implying that viral exploitation of this pathway is evolutionary advantageous. We now show that the β-herpesvirus murine cytomegalovirus (MCMV) takes advantage of the CD200R inhibitory pathway to persist within a mucosal site of MCMV persistence, the salivary glands. Mice deficient in CD200R mounted elevated antiviral immune responses that were driven by the increased division and accumulation of myeloid cells that function to orchestrate the generation of antiviral effector immune responses. Interestingly, MCMV infection of myeloid cells up-regulated CD200 expression. Thus, MCMV exploits the CD200 pathway to persist within mucosal tissue.
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