Progesterone Levels Associate with a Novel Population of CCR5+CD38+ CD4 T Cells Resident in the Genital Mucosa with Lymphoid Trafficking Potential

Abstract

The female genital tract (FGT) provides a means of entry to pathogens, including HIV, yet immune cell populations at this barrier between host and environment are not well defined. We initiated a study of healthy women to characterize resident T cell populations in the lower FGT from lavage and patient-matched peripheral blood to investigate potential mechanisms of HIV sexual transmission. Surprisingly, we observed FGT CD4 T cell populations were primarily CCR7hi, consistent with a central memory (TCM) or recirculating memory T cell phenotype. In addition, roughly half of these CCR7hi CD4 T cells expressed CD69, consistent with resident memory T cells (TRM), while the remaining CCR7hi CD4 T cells lacked CD69 expression, consistent with recirculating memory CD4 T cells that traffic between peripheral tissues and lymphoid sites. HIV susceptibility markers CCR5 and CD38 were increased on FGT CCR7hi CD4 T cells compared to blood, yet migration to the lymphoid homing chemokines CCL19 and CCL21 was maintained. Infection with GFP-HIV showed that FGT CCR7hi memory CD4 T cells are susceptible HIV targets, and productive infection of CCR7hi memory T cells did not alter chemotaxis to CCL19 and CCL21. Variations of resident CCR7hi FGT CD4 T cell populations were detected during the luteal phase of the menstrual cycle and longitudinal analysis showed the frequency of this population positively correlated to progesterone levels. These data provide evidence women may acquire HIV through local infection of migratory CCR7hi CD4 T cells and progesterone levels predict opportunities for HIV to access these novel target cells.

Distinct peripheral vs mucosal T‐cell phenotypes in chlamydia‐infected women

“…Overall, our evaluation of homing markers suggests CCR5 but not CXCR3 in humans may be a key marker for homing of effector T‐cells to the genital tract for an adaptive immune response against CT. While CCR7 is an important homing and memory marker, our finding of a low frequency of CCR7 expression at the genital mucosa is consistent with the idea that CCR7 is downregulated once cells exit the lymphatic system and enter mucosal tissues, perhaps due to a shift toward these cells becoming tissue resident memory (Trm) T‐cells. Due to the limited number of fluorescence channels in our flow cytometer and limited number of viable mucosal mononuclear cells, we were unable to test additional markers that could further differentiate memory cell populations (CD45RA and CD62L) and also markers that allow us to evaluate for Trm T‐cells; this is a future research interest.…”

“…We then evaluated expression of homing chemokine receptors (CKRs) at the peripheral blood vs mucosal site anticipating a lower proportion of these CKRs at the mucosa due to downregulation of these receptors upon arrival at the site of infection. We found lower expression of CCR7, an important T lymphocyte homing and memory marker, in the genital mucosa for both CD4 + and CD8 + cells (both P = .0002) (Figure C). We found no significant difference in the expression of CXCR3, a marker of effector and memory cells that is also important in T‐cell trafficking, on CD4 + cells between compartments; however, CXCR3 expression on CD8 + cells trended toward being higher in the peripheral blood ( P = .0771) (Figure C).…”

The HIV-1 transmission bottleneck

“…It has been suggested that transcytosis and intraepithelial transmigration of infected donor cells are the common mechanisms that the virus uses to access the submucosal tissues of the host. In addition to this, HIV-1 can infect intra-epithelial Langerhans’ cells [54, 55] and also possibly intra-epithelial CCR5 + CCR7 hi CD4 + T cells that can migrate in and out of the female genital tract and hence can disseminate infection [56]. …”

“…It is possible that these latter studies were underpowered to detect the association; perhaps they failed to have a sufficient number of cases of the particular STIs most responsible for the observed increased risk of multivariant transmission. These effects could be mediated by breaks in the integrity of the mucosal barrier [94], inflammatory cytokines [39] and/or availability of more, better or more accessible target cells for HIV-1 [91], particularly cells capable of sustaining HIV-1 infection and migration to other tissues [54–56]. These possibilities may not necessarily be mutually exclusive.…”

Chronic immune barrier dysregulation among women with a history of violence victimization

“…MHCII + APC populations expressed properties associated with increased peripheral tissue trafficking and increased tolerogenic DC subsets, which can promote T cell-mediated immune suppression through directing Treg versus effector T cell differentiation (15)(16)(17). Corresponding to this observation, CD4 + T cells exhibited greater CCR7 expression, which identifies T cells in the skin and HIV target cells in the lower FRT (migratory or recirculating memory T cells) that can reenter afferent lymphatic circulation (11,26). A marked decrease of CD4 + and CD8 + T cell populations expressing tissue retention characteristics was observed, consistent with recent immigration of T cells from the circulation that are not specialized to function in tissue immune surveillance (10,27).…”