Differential localization of distinct CD4 T cell subsets in the female genital tract during the menstrual cycle is regulated by CCR5

Abstract

Abstract CD4 T cells are essential for optimal immune responses against sexually transmitted infections, yet the composition of the CD4 T cell pool localized in the female genital tract (FGT), and the impact of the menstrual cycle on the CD4 T cell population dynamics in the FGT, remains poorly defined. Here we show the FGT CD4 T cell pool is comprised of distinct subsets of memory CD4 T cells based upon trafficking profile, anatomic regionalization, and effector responses. Based on expression of trafficking and tissue retention markers, FGT CD4 T cells are comprised of both migratory memory (TMM) and resident memory (TRM), with TMM expressing a broad array of trafficking markers that would enable their ability to perform immune surveillance in diverse tissues. Furthermore, these subsets differ in both their regionalization throughout the FGT and in their cytokine responses, notably IL-2 production. The frequency of TMM in the FGT increased during the luteal phase of the menstrual cycle and correlated with increased CCR5 expression on circulating memory CD4 T cells. Using a dual adoptive transfer mouse model, we observed that CCR5-mediated trafficking was required for the localization of memory CD4 T cells to the luminal surface of the FGT. In addition, to test cycle influence on T cell trafficking into the FGT, we administered a CCR5 antagonist to pigtail macaques at different stages of the menstrual cycle and found that inhibition of CCR5 signaling selectively reduced TMM numbers solely at luteal time points. Together, these data provide broader insight into role that distinct tissue resident CD4 T cell subsets play in barrier defenses at the FGT and also demonstrate a role for the menstrual cycle in modulating immune protection through CCR5 signaling.