Characterization of a Human Cervical CD4+ T Cell Subset Coexpressing Multiple Markers of HIV Susceptibility

Abstract

The HIV pandemic disproportionately affects women, with most infections acquired through receptive vaginal sex. Although the target cells by which HIV establishes infection in the female genital tract remain poorly defined, it is known that immune activation results in CD4+ T cells with enhanced susceptibility, as does expression of the mucosal integrin α4β7 and the HIV coreceptor CCR5. Blood and cervical cytobrush specimens were collected from female sex workers (FSWs) in Nairobi, Kenya. Genital infection diagnostics were performed, T cell populations were defined by multiparameter flow cytometry based on their expression of surface receptors relevant to mucosal homing and/or HIV acquisition, and cytokine production was assayed by intracellular cytokine staining. The integrin α4β7 was expressed on 26.0% of cervical CD4+ T cells, and these cells were more likely to express both the HIV coreceptor CCR5 (p < 0.0001) and the early activation marker CD69 (p < 0.0001) but not CXCR4 (p = 0.34). Cervical Th17 frequencies were enhanced compared with blood (7.02 versus 1.24%; p < 0.0001), and cervical IL-17A+ CD4+ T cells preferentially coexpressed α4β7 and CCR5. Expression of IFN-γ and IL-22 was greater in cervical Th17 cells than in blood Th17 cells. In keeping with the hypothesis that these cells are preferential HIV targets, gp120 preferentially bound CCR5+ cervical T cells, and cervical Th17 cells were almost completely depleted in HIV+ FSWs compared with HIV− FSWs. In summary, a subset of Th17 CD4+ T cells in the cervical mucosa coexpresses multiple HIV susceptibility markers; their dramatic depletion after HIV infection suggests that these may serve as key target cells during HIV transmission.

Stable CD4 Expression and Local Immune Activation in the Ectocervical Mucosa of HIV-Infected Women

“…Furthermore, local immune activation in the ectocervix of the HIV + women was shown by upregulated cellular markers and cytokine expression. Many studies have described CD4 cell subpopulations and inflammatory markers in cervical mononuclear cell preparations and in cervi- covaginal secretions of HIV + women (12,21,(31)(32)(33). However, this is, to our knowledge, the first report of expression in situ of these immune markers in genital tissues of HIV + women.…”

“…The cells are all heterogeneous with regard to HIV susceptibility, which is critically dependent on the presence of the major HIV coreceptor CCR5 (7,(11)(12)(13)(14). Also, other classes of HIV-binding molecules, including the C-type lectin receptors (CLRs), have implications for HIV susceptibility and are present on mucosal macrophages and subpopulations of DCs.…”

Role of Semen in Modulating the Female Genital Tract Microenvironment – Implications for HIV Transmission

“…CD4 + Th17 cells are among the earliest HIV/SIV preferential targets and play a crucial role in HIV pathogenesis. 86,[94][95][96][97] In contrast to the significant semen-induced increase in DCs and LCs in the female genital epithelium, no or modest increases in FRT CD4 + T cell density have been detected following semen exposure. 23,38 At the same time, due to CCL20, a small number of these highly susceptible to HIV-1 CD4 + Th 17 cells can infiltrate the mucosal epithelium or migrate to local lymph nodes.…”

Dimorphic HLA-B signal peptides differentially influence HLA-E- and natural killer cell-mediated cytolysis of HIV-1-infected target cells

“…The target cells that initiate HIV-1 infection at the genital mucosa are most likely central memory CD4 cells and macrophages [36][37][38][39], with potential assistance by dendritic cells [40]. As dendritic cells do not support viral replication, our experiments focused on HIV-1 infection in CD4 cells and MDMs.…”