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Edited by John J. Eppig, The Jackson Laboratory, Bar Harbor, ME, and approved December 22, 2014 (received for review July 16, 2014)
Significance
In natural matings, semen delivers spermatozoa and immunoregulatory fluids to the female reproductive tract. Here, a soluble form of CD38 (sCD38) is shown to play an important role in facilitating maternal immune tolerance against the fetus by inducing the development of uterine tolerogenic DCs and forkhead box P3+ (Foxp3+) regulatory T cells. Deficiency of sCD38 in seminal fluid increased the rates of loss of allogeneic fetuses, and this loss was rescued by a direct injection of recombinant sCD38 into the uterus. Thus, seminal sCD38 acts as a pivotal immune suppressor for establishing maternal immune tolerance against the fetus. sCD38 could potentially be used to prevent failed pregnancies.
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.
Footnotes
- ↵1To whom correspondence should be addressed. Email: uhkim{at}chonbuk.ac.kr.
Author contributions: B.-J.K. and U.-H.K. designed research; B.-J.K., Y.-M.C., S.-Y.R., D.-R.P., S.-A.P., Y.-J.C., S.-M.P., J.K.P., and K.Y.J. performed research; B.-J.K., K.Y.J., and U.-H.K. analyzed data; and B.-J.K. and U.-H.K. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1413493112/-/DCSupplemental.
Seminal CD38 induces fetomaternal tolerance
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