CD161 identifies a subset of circulating Th17 cells that are depleted in the blood and gut of HIV-infected individuals. T cells in the FRT with a predominance of polyfunctional Th1/Th17 cells. Here, we showed that the expression of CD161 on CD4+T cells is usually modulated at the FRT, but still identified a highly activated cellular subset, which differentiates into pro-inflammatory Th1/Th17 cells, expresses multiple 1561178-17-3 supplier HIV susceptibility markers and are depleted in HIV-infected individuals. The use of CD161 as a biomarker of HIV targets in the FRT reduces the need for functional assessment of cells and could have important implications in better understanding HIV pathogenesis and Th17 fate in the FRT of high-risk women. Introduction In 2015, fifty-six percent of new HIV infections in sub-Saharan Africa were among women and this number continues to grow disproportionally1, reinforcing the importance of bringing scientific attention to womens health. The female reproductive tract (FRT) is usually characterized by the presence of several innate mucosal factors that 1561178-17-3 supplier exert effective defences against HIV entry2. However, this protective role can be disrupted by inflammation-driven breaches in the mucosal defence, which facilitates HIV penetration into the genital mucosa. Factors driving or sustaining inflammation at the FRT are believed to promote HIV contamination through the activation and recruitment of CD4+ T cells3, 4. However, we do not yet fully understand the landscape of HIV targets in the genital tract and the factors regulating their recruitment and activation. CD161 is usually a type II transmembrane glycoprotein, a member of the C-type lectin family and a recognized biomarker of the T helper 17 lineage5C7. IL-17-producing cells differentiate from CD161 precursors and maintain the expression of CD161 throughout their life cycle, comprising 20% of the circulating7, 8 and 60% of the colonic lamina propria CD4+ T lymphocytes5, 9. CD161+CD4+ T cells exhibit an effector memory phenotype with a transcriptional profile including Th17 signature genes such as and or CD161+CD4+ T cells between untreated chronically HIV-infected FSWs (n?=?16) and HIV-uninfected FSWs (n?=?69). We observed a diminution of the mean proportion of cervical CD161+CD4+ T cell in HIV-infected FSWs compared to the mean proportion among HIV-negative FSWs (P?=?0.009)(Fig.?4a) in addition to an overall depletion of the proportion of cervical CD4+ T cells in the CD3+ compartment (Fig.?4b, P?0.0001). This specific depletion was unique to the FRT as in the blood, the proportion of circulating CD161+CD4+ T cells 1561178-17-3 supplier was comparable between HIV-infected and uninfected FSWs despite the obvious depletion of CD4 lymphocytes (Fig.?4c,d). This observation is usually in agreement with previous observation that Th17 cells in the FRT are depleted during HIV contamination11, 17. Physique 4 Comparison of the proportion of (a) CD161+ cells in the cervical CD4+ T cell compartment, (b) CD4+ T cells in the cervical CD3+ T cell compartment, (c) CD161+ cells in the systemic CD4+ T cell compartment, and (d) absolute plasma CD4 count between HIV-negative 1561178-17-3 supplier … Discussion Susceptibility to HIV infection is highly dependent on the degree of cervical inflammation26. Sex hormones, genital infections and bacterial microflora all regulate the genital microenvironment Rabbit Polyclonal to Cyclin H and its downstream effect on the recruitment of HIV targets4, 24, 27, 28. Inflammation in the FRT is the result of a complex interplay between epithelial and immune cells and a comprehensive portrait of this inflammatory landscape is still lacking. The documented role of CD161-expressing CD4+ T lymphocytes in pathogenic auto-immunity5, 13C15 and their lineage commitment to Th17 cells, make them a likely candidate to enhance HIV susceptibility through modulating the inflammatory environment, or more directly, by acting as HIV targets at the portal of entry. We explored, for the first time, the phenotype and inflammatory profile of CD161+CD4+ lymphocytes at the FRT. We report an enrichment of the CD161+ fraction among the cervical T helper cells in the FRT and this finding aligns closely with the reported increase in IL-17-expressing cells previously observed11, 12. We also observed that the CD4+ T cells identified by CD161 in the FRT differ in nature and.