Seminal CD38 is a pivotal regulator for fetomaternal tolerance

Abstract

A successful pregnancy depends on a complex process that establishes fetomaternal tolerance. Seminal plasma is known to induce maternal immune tolerance to paternal alloantigens, but the seminal factors that regulate maternal immunity have yet to be characterized. Here, we show that a soluble form of CD38 (sCD38) released from seminal vesicles to the seminal plasma plays a crucial role in inducing tolerogenic dendritic cells and CD4+ forkhead box P3 + (Foxp3 + ) regulatory T cells (Tregs), thereby enhancing maternal immune tolerance and protecting the semiallogeneic fetus from resorption. The abortion rate in BALB/c females mated with C57BL/6 Cd38 −/− males was high compared with that in females mated with Cd38 +/+ males, and this was associated with a reduced proportion of Tregs within the CD4 + T-cell pool. Direct intravaginal injection of sCD38 to CBA/J pregnant mice at preimplantation increased Tregs and pregnancy rates in mice under abortive sonic stress from 48 h after mating until euthanasia. Thus, sCD38 released from seminal vesicles to the seminal plasma acts as an immunoregulatory factor to protect semiallogeneic fetuses from maternal immune responses.eventy-five percent of pregnancies that are lost represent failure of implantation and are therefore not clinically recognized as pregnancies (1). Recurrent miscarriage (the spontaneous loss of three or more consecutive pregnancies) is a significant health issue for 1-2% of women, with no identifiable biological cause and no effective treatment. During early stages of pregnancy, complex processes help to create a uterine environment that is conducive to a successful pregnancy. These include immunological adaptation to the semiallogeneic fetus. Tolerance to paternal alloantigens is critical for successful reproduction in placental mammals (2, 3). Many studies have proposed that regulatory T cells (Tregs) play an essential role in the development of fetomaternal tolerance in mice and humans (4-7). 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 (8-10). However, the specific molecules in semen that are responsible for expansion of Tregs and establishment of maternal tolerance remain undefined.CD38, a mammalian prototype of ADP ribosyl cyclases (ADPRCs), is a type II transmembrane (TM) glycoprotein expressed in many cell types and seminal fluid (11-16). CD38 produces calcium-mobilizing second messengers, cyclic ADP ribose, and nicotinic acid adenine dinucleotide phosphate (11, 12). We previously showed that intact CD38 in prostasomes assists progesterone-induced sperm Ca 2+ signaling (13). In addition to its enzymatic role for Ca 2+ signaling, CD38 may also have a nonenzymatic role through its interaction with CD31 (17, 18). CD31, a type I TM homophilic or heterophilic receptor, is expressed in endothelial cells and a variety of immune cells (19) and is involved in attenuating the infl...

What is wrong with the regulatory T cells and foetomaternal tolerance in women with recurrent miscarriages?

“…More specifically, a soluble form of CD38 (sCD38) released from seminal vesicles to the seminal plasma might play a role in this process. Soluble CD38 in seminal plasma was shown to be crucial for the induction of uterine tolerogenic dendritic cells (DCs) and CD4+Foxp3+ Tregs . Deficiency of sCD38 in seminal fluid increased the loss rate of allogeneic foetuses, which could be rescued by a direct injection of recombinant sCD38 into the uterus.…”

Regulatory T Cells Orchestrate Similar Immune Evasion of Fetuses and Tumors in Mice

“…Thus, unsupervised purely statistical generation of signatures appears more sensitive than supervised methods and may reveal early changes of immune-annotated signatures that could be related to Treg activation by seminal fluid (55). A recent study demonstrated that a soluble form of CD38 released from seminal vesicles induces tolerogenic DCs and activates Tregs, thereby enhancing maternal immune tolerance and protecting the fetus from rejection (56).…”

Mechanisms of maternal tolerance to the fetus: lessons of molecular diplomacy

“…Фаллопиевы трубы, в которых происходит оплодотворение, содержат фак-торы, подавляющие активность системы компле-мента -CD46, CD55, CD59 [4] и препятствуют ком-плементопосредованному лизису раннего эмбриона при наличии у матери антител к МНС антигенам от-ца, вызванных иммунизацей в ходе предыдущей бе-ременности. В семенной плазме обнаружены раство-римые факторы, такие как TGF-β и CD38, которые, вероятно, участвуют в подготовке матки к толерант-ности, и при отсутствии которых частота успешных зачатий снижается [5,6].…”

“…Фаллопиевы трубы, в которых происходит оплодотворение, содержат фак-торы, подавляющие активность системы компле-мента -CD46, CD55, CD59 [4] и препятствуют ком-плементопосредованному лизису раннего эмбриона при наличии у матери антител к МНС антигенам от-ца, вызванных иммунизацей в ходе предыдущей бе-ременности. В семенной плазме обнаружены раство-римые факторы, такие как TGF-β и CD38, которые, вероятно, участвуют в подготовке матки к толерант-ности, и при отсутствии которых частота успешных зачатий снижается [5,6].Преимплантационный эмбрион также не экс-прессирует молекул МНС и, вдобавок, окружен zona pellucida, которая защищает его от гуморальных фак-торов иммунитета, таких как антитела. После при-крепления в матке фертилизационная мембрана рас-творяется, и эмбрион становится чувствительным к иммунной атаке.…”