Immunology of Uterine and Vaginal Mucosae: (Trends in Immunology 39, 302-314, 2018)

Abstract

Along with maintaining symbiotic mutualism with commensal microbes and protection against invasive infections common to all mucosal barrier tissues, female reproductive tissues have additional unique tasks that include dynamic cyclic cellular turnover in menstruation and immunological tolerance to genetically foreign fetal antigens in pregnancy. Herein, we review current knowledge on distinct features of the immune cells in the female reproductive tissue with regards to antimicrobial host defense and adaptations to accommodate the fetus during pregnancy. Outstanding areas for future research to shed new functional insights on this enigmatic mucosal barrier is also highlighted.

Figure 1. The immunology of the cervicovaginal and non-pregnant uterine mucosae

(A) The cervicovaginal mucosa maintains homeostasis with the vaginal microbiome, composed primarily of Lactobacillus, while, at the same time, surveying for pathogens. In the human cervicovaginal mucosa, 4 major myeloid APCs were described, with epithelial cvLCs and CD14⁻ LP-DCs showing gene signatures associated with tolerogenic or T_H2-inducing functions. Additionally, plasma cells participate in immune defense by secreting IgG, IgA and IgM. Most CD4⁺ and CD8⁺ T cells in the cervicovaginal mucosa are tissue-resident memory (T_RM) cells which can confer rapid immmune protection against pathogens by producing IFN-γ and eliciting epithelial production of the chemokines CXCL9 and CXCL10 to activate the mucosal endothelium and recruite additional immune cells. (B) The human cervix harbors many effector and effector memory CD4⁺ and effector CD8⁺ T cells, and to a lesser extent, B cells, NK cells, DCs and monocytes/macrophages. (C) Many of the innate immune cell types, such as macrophages, neutrophils and NK cells, are involved in facilitating the structural and physiological changes during the menstrual cycle via the production of chemokines, proteases and angiogenic factors. Additionally, macrophage are involved in the formation of lymphoid aggregates and may participate in antigen presentation and assisting CD8⁺ T and B cell activation. The function of the lymphoid aggregates in the human uterus is currently unclear, but may be involved in antigen scavenging and antibody production. Some of the information presented in the figure was extrapolated from mouse studies.

Figure 2. The immunology of the decidua basalis and choriodecidua during pregnancy

(A) dNK cells are a major immune cell type in human early decidua basalis. They crosstalk with decidual DCs and EVTs, and are diverted from a cytotoxic fate to an alternative one with the production of angiogenic and immunomodulatory factors that are optimal for placentation and fetal tolerance (a scenario also seen in decidual macrophages). dNK cells can be regulated by invading EVTs expressing MHC-I molecules, such as HLA-G, which can engage the inhibitory NK receptors. Neutrophils that are of an alternative phonetype found in this tissue could promote blood vessel remodeling by producing angiogenic factors. Additionally, Tregs are essential for the establishment and maintenance of fetal tolerance through the inhibition of effector and inflammatory cell types. (B) In addition to T cells, macrophages and neutrophils present in the human middle and late pregnancy choriodecidua, B cells recently found in this tissue can respond to tissue stress signals, such as IL-33, and, in response, secrete PIBF1 to suppress decidual inflammation and offer protection against the ensuing premature onset of labor. Tregs are also present in the choriodecidua and can inhibit inflammation and promote fetal tolerance. Some of the information presented in the figure was extrapolated from mouse studies.