The Mammalian Zona Pellucida: A Matrix That Mediates Both Gamete Binding and Immune Recognition?

The crucial cell adhesion events required for mammalian fertilization commence when spermatozoa bind to the specialized extracellular matrix of the oocyte, known as the zona pellucida (ZP). Bound gametes then undergo a signal transduction cascade known as acrosomal exocytosis that enables them to penetrate this matrix and fuse with the oocyte to create a new individual. The ZP is therefore the target of intense investigation in the mouse, pig, bovine, and human models. Major goals in such studies are to define the adhesion molecules, signal transduction pathways, and the molecular basis for the species-restricted binding of gametes. Evidence exists indicating that protein-carbohydrate and to a lesser extent protein-protein interactions play a role in the initial gamete binding. More recent findings in an unusual sperm-somatic cell adhesion system indicate that tri- and tetraantennary N-glycans mediate initial sperm-oocyte binding in both the murine and porcine models, but conflicting data exist. A novel paradigm designated the "domain specific model'' will be presented that could explain these inconsistencies. Another potential functional role of the ZP is immune recognition. Both spermatozoa and oocytes lack major histocompatibility (MHC) class I molecules that mediate the recognition of self in the immune system. This absence makes gametes less susceptible to class I restricted cytotoxic T lymphocytes, but more vulnerable to natural killer (NK) cells. Therefore a "fail safe'' system for NK cell recognition should exist on both types of gametes. Another issue is that oocytes could begin to express paternal major histocompatibility antigens during the blastocyst stage prior to hatching, and thus mechanisms could also be in place to block the development of maternal adaptive immune responses. An enhanced understanding of these issues could facilitate the development of superior infertility treatments and contraceptive strategies, and define central operating principles of immune recognition in the female reproductive system.