Dendritic cells from the human female reproductive tract rapidly capture and respond to HIV

Abstract

Dendritic cells (DCs) throughout the female reproductive tract (FRT) were examined for phenotype, HIV capture ability and innate anti-HIV responses. Two main CD11c+ DC subsets were identified: CD11b+ and CD11blow DCs. CD11b+CD14+ DCs were the most abundant throughout the tract.A majority of CD11c+CD14+ cells corresponded to CD1c+ myeloid DCs while the rest lacked CD1c and CD163 expression (macrophage marker) and may represent monocyte-derived cells. Additionally we identified CD103+ DCs, located exclusively in the endometrium, while DC-SIGN+ DCs were broadly distributed throughout the FRT. Following exposure to GFP-labeled HIV particles, CD14+ DC-SIGN+ as well as CD14+ DC-SIGN- cells captured virus, with approximately 30% of these cells representing CD1c+ myeloid DCs. CD103+ DCs lacked HIV capture ability. Exposure of FRT DCs to HIV induced secretion of CCL2, CCR5 ligands, IL-8, elafin and SLPI within 3h of exposure, while classical pro-inflammatory molecules did not change and IFNα2 and IL10 were undetectable. Furthermore, elafin and SLPI up-regulation, but not CCL5, were suppressed by estradiol pretreatment. Our results suggest that specific DC subsets in the FRT have the potential for capture and dissemination of HIV, exert antiviral responses and likely contribute to the recruitment of HIV-target cells through the secretion of innate immune molecules.

Aging impacts CD103+CD8+ T cell presence and induction by dendritic cells in the genital tract

“…Since CD103 + T cells co‐stained for CD69 (Figure S1b), consistent with previous reports (Posavad et al., 2017), we focused our studies on the CD103 + CD3 + T cell subset. Consistent with our previous observations (Rodriguez‐Garcia et al., 2017), CD103 + T cells were present at the three sites analyzed with no significant differences between upper and lower FRT (Figure 1b). To investigate potential changes after menopause in the percentage of CD3 + T cells that were CD103 + , results from Figure 1b were stratified according to menopausal status (characteristics of the patients shown in Table 1).…”

“…To evaluate whether FRT DCs regulate CD103 + T cells, DCs purified from the EM were tested for their ability to induce CD103 expression on allogeneic naïve T cells. DCs were purified using CD1a‐ or CD14‐positive selection as previously described (Rodriguez‐Garcia et al., 2017), to examine whether different FRT DC populations are functionally similar. Naïve T cells purified from blood expressed very low levels of CD103 at day 0 (Figure 2a), consistent with previous publications (Rosato et al., 2017).…”

“…Importantly, while DC's ability to upregulate CD103 was affected by menopausal status, their ability to induce T‐cell proliferation was not, suggesting a very selective regulation of DC function. The selectivity of this mechanism is further supported by our previously reported lack of changes in DC phenotype and HIV‐capture potential between pre‐ and postmenopausal women (Rodriguez‐Garcia et al., 2017). While we did prove the ability of endometrial DCs to induce the expression of CD103 on naïve T cells, whether DCs have the ability to modify CD103 expression levels on tissue memory T cells remains to be investigated.…”

“…In the FRT, more than 95% of T cells are effector memory (Saba et al., 2010; Yeaman et al., 1997), with a high proportion of T cells expressing CD103 in the vagina, endocervix (CX), ectocervix (ECX), and endometrium (EM) (Duluc et al., 2013; Moylan et al., 2016; Rodriguez‐Garcia et al., 2017). Along with resident T cells, mucosal surfaces are populated by multiple subsets of resident DCs critical for the induction and maintenance of T‐cell responses (Schlitzer, McGovern & Ginhoux, 2015).…”

“…DCs are known to be strongly influenced by the tissue environment, regarding their numbers, phenotype, and function (Schlitzer et al., 2015). We recently described a compartmentalized distribution of DCs in the FRT, with specific DC subsets restricted to the EM, while other subsets were distributed throughout the upper and lower FRT (Rodriguez‐Garcia et al., 2017). Studies with human DCs from the lung and vaginal mucosa demonstrate that certain DC subsets can induce CD103 + T cells with tissue‐resident characteristics (Duluc et al., 2013; Yu et al., 2013), suggesting that tissue DCs have the ability to control mucosal accumulation of TRMs.…”