Semen Promotes the Differentiation of Tolerogenic Dendritic Cells

Abstract

Seminal plasma is not just a carrier for spermatozoa. It contains high concentrations of cytokines, chemokines, and other biological compounds that are able to exert potent effects on the immune system of the receptive partner. Previous studies have shown that semen induces an acute inflammatory response at the female genital mucosa after coitus. Moreover, it induces regulatory mechanisms that allow the fetus (a semiallograft) to grow and develop in the uterus. The mechanisms underlying these regulatory mechanisms, however, are poorly understood. In this study, we show that seminal plasma redirects the differentiation of human dendritic cells (DCs) toward a regulatory profile. DCs differentiated from human monocytes in the presence of high dilutions of seminal plasma did not express CD1a but showed high levels of CD14. They were unable to develop a fully mature phenotype in response to LPS, TNF-α, CD40L, Pam2CSK4 (TLR2/6 agonist), or Pam3CSK4 (TLR1/2 agonist). Upon activation, they produced low amounts of the inflammatory cytokines IL-12p70, IL-1β, TNF-α, and IL-6, but expressed a high ability to produce IL-10 and TGF-β. Inhibition of the PG receptors E-prostanoid receptors 2 and 4 prevented the tolerogenic effect induced by seminal plasma on the phenotype and function of DCs, suggesting that E-series PGs play a major role. By promoting a tolerogenic profile in DCs, seminal plasma might favor fertility, but might also compromise the capacity of the receptive partner to mount an effective immune response against sexually transmitted pathogens.

A role for seminal plasma in modulating pregnancy outcomes in domestic species

“…In addition, Kim and colleagues have identified SP-derived soluble CD38 as the active factor to induce the production of these important Treg cells and when depleted from the ejaculate of mice pregnancy failure ensued (Kim et al 2015). Others have demonstrated the importance of SP-derived prostaglandins in expanding tolerogenic dendritic cells thought to be important in immune tolerance of pregnancy (Remes Lenicov et al 2012). The critical role for SP-derived changes to the immune system stretch beyond what is presented here, but what does this imply for current assisted reproductive techniques and pathologies of pregnancy?…”

Adaptive Immune Responses During Pregnancy

“…In vitro, human seminal fluid can keep human DCs in a tolerogenic status 28 and promote the induction of Treg phenotype in T cells. 19 Understanding the molecules involved in this will help improving IVF protocols.…”

Seminal CD38 is a pivotal regulator for fetomaternal tolerance

“…Even in the absence of fertilization, exposure of the female genital tract to seminal plasma induced tolerance to the paternal alloantigen via expansion of Foxp3 + Tregs (8,37). Seminal plasma confers DCs with immunoregulatory potential, and these DCs are crucial for embryo implantation and the generation of Tregs (9,10,34,38). Seminal fluid contains high levels of TGF-β (39,40) and prostaglandins (41), both of which have been proposed to contribute to the induction of Foxp3 + Tregs and/or the differentiation of tDCs (9,42).…”

“…Previous studies suggest that seminal factors promote the generation of tDCs (9,10). Therefore, we next examined whether seminal sCD38 inhibited the insemination-induced maturation of uterine DCs by comparing phenotypic maturation markers on uterine DCs in wild-type and Cd38 −/− matings.…”

“…Many studies have proposed that regulatory T cells (Tregs) play an essential role in the development of fetomaternal tolerance in mice and humans (4)(5)(6)(7). Seminal plasma contains potent immunoregulatory molecules that contribute to the induction of tolerogenic DCs (tDCs) and ultimately Treg expansion, which is necessary to establish maternal tolerance against paternal antigens (8)(9)(10). However, the specific molecules in semen that are responsible for expansion of Tregs and establishment of maternal tolerance remain undefined.…”