Migratory memory CD4 T cells surveilling the lower reproductive tract direct rapid clearance of Chlamydia muridarum following vaginal challenge

Abstract

Abstract Despite their importance for immunity against sexually transmitted infections, the regulation and function of CD4 T cells in the female reproductive tract (FRT) remains poorly defined. Here we show that across human, non-human primate, and mouse species the FRT memory CD4 T cell pool consists of distinct subsets corresponding to migratory (TMM) and resident (TRM) memory T cells. TMM in the FRT exhibit broad expression of trafficking molecules, restricted distribution to discreet areas of the FRT, and differential responses to local infection. To investigate the contribution of TMM to protective immunity in the FRT, we constructed an influenza virus (HK/x-31) expressing an immunodominant CD4 T cell epitope from the Chlamydia muridarum probable outer membrane protein (PmpG-1303–311). C57Bl/6 mice were infected intranasally with x31-PmpG1 to generate PmpG1-specific CD4 TMM and investigate their ability to surveil distant mucosal tissues. PmpG1-specific CD4 T cells were found restricted into the lower, but not upper, FRT and expressed chemokine receptors and adhesion molecules consistent with TMM. Vaginal challenge of x31-PmpG1 memory mice with C. muridarum showed a significant decrease in bacterial burden at 14 days post-infection (dpi), when bacterial clearance was first detectable in naïve control mice. Notably, x31-PmpG1 memory mice treated with FTY720 during the initial stages of C. muridarum challenge failed to limit bacterial growth, suggesting this effect was due in part to TMM localization to the FRT. These data show that vaccinating at distant mucosal sites can generate surveilling CD4 TMM cells that are distinct from classical central, effector and resident memory CD4 T cells, and can protect against pathogens in the FRT.