Seminal Advances in Immunology of Reproduction

Abstract

INTRODUCTION The paper by Guerin et al. from Sarah Robertson’s group in this issue of Biology of Reproduction reports a major advance in our understanding of the mechanism(s) by which male semen may protect the implanting semi-allogeneic embryo against rejection by maternal innate and adaptive immune defenses. BALB/c (H-2) males were used with C56BL6 (H-2) females [1]. Following mating, the lymph nodes draining the uterus, (draining lymph nodes, DLN or para-aortic lymph nodes PALN) enlarge; this enlargement is greater when the male is allogeneic. i.e. histoincompatible with the female, and generation of anti-paternal cytotoxic T cells is suppressed [2]. The sequence of events is depicted in Figure 1. Seminal plasma (SP) and spermatozoa (S) ejaculated into the uterine lumen at the time of mating on gestation day 0 (GD 0) act on the uterine epithelium, sub-endothelial macrophages (Mph) and dendritic cells (DC). This leads to trafficking of cells (and perhaps the predominant chemokine CCL19) via afferent lymphatics to para-aortic lymph nodes draining the uterus (DLN or PALN). There, CCL19 recruits circulating regulatory T cells (Treg, identified by the presence of FOXP3) acting via the CCR7 receptor (and possibly CCR5) . DC may present antigens from SP (blue dots) or spermatozoa (red dots). Activated Treg cells exit the lymph nodes and home tothe uterine lining by GD day 3.5, again mediated for the most part by CCL19 binding to CCR7. Interestingly, measuring mRNA for Foxp3 showed an increase that was reduced by about half if SVX males lacking seminal plasma (SP) or VAS males lacking spermatazoa (S) were used, suggesting spermatozoa could activate Foxp3 mRNA in uterine cells without significantly increasing CCL19-dependent Treg cell recruitment, although both S+SP were required for maximal activation. On GD 4.5, the semi-allogeneic blastocyst, potentially susceptible to rejection directed against minor paternal histocompatibility antigens [2], implants. Guerin et al. argue that the regional generation and local recruitment of Treg cells to the uterus in advance of implantation acts to protect the implanting embryo against maternal immune rejection. In support of this contention, they noted an increase in CD4CD25 cells in the DLN that did not express FOXP3 and which could represent activated effector T cells.