CD101 Genetic Variants Modify Regulatory and Conventional T-Cell Phenotypes and Functions

We recently reported that risk of sexually-acquired HIV-1 infection is significantly increased by variants in the gene encoding CD101, a protein thought to modify inflammatory responses. Using blood samples from individuals with versus without these variants, we now demonstrate that CD101 variants modify the prevalence of diverse circulating inflammatory cell types, and show that CD101 variants are associated with increased proinflammatory cytokine production by circulating T-cells. Further, one category of CD101 variants was associated with a reduced capacity of regulatory T-cells to suppress CD4+ T-cell cytokine production, resulting in a hypothesized loss of baseline immune quiescence. These data were supported by transcriptomic data revealing alterations in the intrinsic regulation of antiviral pathways and HIV-resistance genes in individauls with CD101 variants. Our data support the hypothesis that CD101 regulates bystander inflammation, with CD101 variants altering heterosexual acquisition of HIV-1 by allowing for increased prevalence and altered function of specific T-cell subsets.