Human cytomegalovirus interleukin 10 (cmvIL-10) orchestrates crosstalk between the cellular IL-10 receptor and CXCR4

Human cytomegalovirus (HCMV) is a widespread beta-herpesvirus that establishes lifelong latent infection in host cells. The HCMV UL111A gene encodes cmvIL-10, a viral homolog of the anti-inflammatory cytokine IL-10 (hIL-10). Like hIL-10, cmvIL-10 binds to the human cellular IL-10 receptor (IL-10R) and activates the JAK/STAT3 pathway, promoting transcription of immunosuppressive genes. Notably, cmvIL-10 binds to the IL-10R with higher affinity than hIL-10 and retains most of its functions, including enhancing CXCR4 signaling triggered by its primary ligand, CXCL12. The CXL12/CXCR4 axis regulates key cellular processes such as gene expression, cell migration, proliferation, and apoptosis. CXCR4 also interacts with alternative ligands including macrophage inhibitory factor (MIF), trefoil factor 2 protein (TFF2), and extracellular ubiquitin (UB). Here, we show that cmvIL-10 enhances CXCR4-mediated cell proliferation and migration induced by MIF and TFF2 but not by UB. We also found that hIL-10 enhances MIF-mediated cell proliferation yet has no effect on TFF2-mediated cell proliferation. The CXCR4 antagonist AMD3100 effectively blocks cell migration driven by TFF2, while only partially inhibiting MIF-mediated cell migration. These results suggest that cmvIL-10 promotes crosstalk between IL-10R and CXCR4, underscoring its role in modulating immune responses during HCMV infection. Our findings provide insight into how cmvIL-10 contributes to immune evasion and pathogenesis in HCMV.