Differential signaling of cmvIL‐10 through common variants of the IL‐10 receptor 1

Human IL‐10 (hIL‐10) signaling is mediated by receptors consisting of two subunits, IL‐10 receptor 1 (IL‐10R1) and IL‐10 receptor 2. Two common variants of the IL‐10R1 (Ser 138 Gly (single‐nucleotide polymorphism 3, SNP3) and Gly 330 Arg (SNP4)) are associated with diverse disease phenotypes. Viral homologs to hIL‐10, such as cmvIL‐10, utilize the same IL‐10 receptor complex as part of viral immune evasion strategies. For the present study we hypothesized that IL‐10R1 variants alter the ability of viral IL‐10 to utilize the IL‐10R1 signaling pathway. HeLa cell clones expressing different IL‐10R1 haplotypes (WT or any variant) were incubated with hIL‐10 or cmvIL‐10. In cells expressing IL‐10R1‐WT, cmvIL‐10 (both non‐glycosylated‐ and HeLa‐expressed) resulted in equal or slightly stronger STAT3 phosphorylation compared with hIL‐10. In clones expressing IL‐10R1‐SNP3, IL‐10R1‐SNP4 or IL‐10R1‐SNP3+4, the cmvIL‐10 showed significantly less STAT3 phosphorylation, especially when HeLa‐expressed cytokines were used. Time course experiments demonstrated a slower kinetic of cmvIL‐10 STAT3 activation through the variant IL‐10R1. Similarly, IL‐10R1 variants decreased the cmvIL‐10‐induced SOCS3 and signaling lymphocytic activation molecule mRNA expression. These data suggest that the IL‐10R1 variants differentially reduce the signaling activity of cmvIL‐10 and thereby may affect CMV's ability to escape from the host's immune surveillance.