Seminal Fluid Regulates Accumulation of FOXP3+ Regulatory T Cells in the Preimplantation Mouse Uterus Through Expanding the FOXP3+ Cell Pool and CCL19-Mediated Recruitment1

Abstract

Regulatory T (Treg) cells facilitate maternal immune tolerance of the semiallogeneic conceptus in early pregnancy, but the origin and regulation of these cells at embryo implantation is unclear. During the preimplantation period, factors in the seminal fluid delivered at coitus cause expansion of a CD4(+)CD25(+) putative Treg cell population in the para-aortic lymph nodes draining the uterus. Using flow cytometry, immunohistochemistry, and real-time quantitative PCR (qPCR) for the signature Treg cell transcription factor FOXP3, we confirmed the identity of the expanded lymph node population as FOXP3(+) Treg cells and showed that this is accompanied by a comparable increase in the uterus of FOXP3(+) Treg cells and expression of Foxp3 mRNA by Day 3.5 postcoitum. Seminal plasma was necessary for uterine Treg cell accumulation, as mating with seminal vesicle-deficient males failed to elicit an increase in uterine Treg cells. Furthermore seminal fluid induced expression of mRNA encoding the Treg chemokine CCL19 (MIP3beta), which acts through the CCR7 receptor to regulate Treg cell recruitment and retention in peripheral tissues. Glandular and luminal epithelial cells were identified as the major cellular origins of uterine CCL19, and exposure to both seminal plasma and sperm was required for maximum expression. Together, these results indicate that Treg cells accumulate in the uterus prior to embryo implantation and that seminal fluid is a key regulator of the uterine Treg cell population, operating by both increasing the pool of available Treg cells and promoting their CCL19-mediated recruitment from the circulation into the implantation site.

Seminal Fluid Induces Leukocyte Recruitment and Cytokine and Chemokine mRNA Expression in the Human Cervix after Coitus

“…This is consistent with previous encounter and priming to seminal fluid Ags, which would be expected in sexually active women not using barrier contraception. This contrasts with experiments in virgin mice, where reproductive tract T cells are less abundant and seminal fluid-induced population expansion requires several days to become detectable (14,34). Notwithstanding the more rapid and predominantly memory T cell response we observed in women, the time frame of this study is not ideal for detecting T cell responses, which generally take .12 h to fully evolve.…”

“…Based on our findings in mice (12,14), we speculate that cervical T cells play a crucial role in the development of tolerogenic immune responses to male transplantation Ags contained within the ejaculate. The phenotype of any T cell response is relevant to the fate of sperm and, thus, future fertility.…”

“…The full effect of seminal fluid on female immune parameters is best characterized in the mouse, where within hours of mating, macrophages, dendritic cells (DCs), and granulocytes are recruited into the endometrial stroma and lumen (3,10,11). Through a process of crosspresentation by female DCs in lymph nodes draining the genital tract, seminal fluid Ags activate and expand inducible regulatory T cell populations (12,13) that subsequently migrate into the endometrium to mediate immune tolerance of the conceptus at implantation (14). The regulatory T cell response to seminal fluid depends on seminal plasma factors originating in the seminal vesicle gland (4), notably TGF-b, which is synthesized in the latent form and activated in the female tract after ejaculation (15).…”

Seminal fluid and reproduction: much more than previously thought

“…Initial studies depleting T-regulator lymphocytes showed a failure of pregnancy due to immune rejection of the conceptus [89]. Our studies have now shown that exposure to seminal plasma at insemination drives expansion of T-regulatory lymphocytes in the PALN and uterus [90].…”

Mucosal Immune Regulation: Does it Help Thwart HIV?

“…Sex itself might be a part of the answer. In a mouse model, seminal fluid regulates the accumulation of Treg at the FGT [130]. Semen contains high concentrations of TGF-b [114,115,131] and exposure to seminal plasma converts naïve T cells into functional FOXP3-negative Treg that secrete TGF-b [132].…”