In the peripheral immune compartment, the vast majority of T cells express a T-cell receptor comprised of an αβ heterodimer (TCRαβ+). In addition to TCRαβ+ T cells, the human reproductive tract also is populated by a subset of T cells with a distinctive T-cell receptor comprised of the γδ heterodimer (TCRγδ+), and the numbers of these cells increases in early pregnancy (139–141). TCRγδ+ T cells appear to fulfill functions quite distinct from their αβ+ counterparts; functions that may include direct, non-MHC restricted recognition of antigens within tissues (142). TCRγδ+ T cells may fill a protective niche that is either missed or poorly covered by B cells and TCRαβ+ T cells. The role and importance of TCRγδ+ cells in the reproductive tract and, more particularly, in pregnancy maintenance deserves further attention.
Treg cells are also of the “suppressor” functional phenotype. In pregnant mice and women, these specialized CD4+ cells are systemically expanded in an alloantigen independent fashion and can suppress adverse maternal responses to the fetus (143) and to self (144).
The human decidua contains characteristic immune effector cells. Most investigations into whether alterations in these cells (including T cells, decidual NK cells, and NKT cells) determine pregnancy outcome are hampered by insufficient patient numbers to allow meaningful conclusions. These immune cell populations are reported to be altered in recurrent pregnancy loss patients but not in patients experiencing isolated spontaneous pregnancy losses (141,145–147).
Immune Cell Education and Homing to the Reproductive Tract The implanting fetus represents the most common model of allograft acceptance. How the maternal immune system avoids rejection of the implanting fetus in an uncomplicated pregnancy invokes the presence of some manifestation of immune tolerance. This, in turn, begs the questions of how the resident decidual immune effector cells are selected and educated, how they home to reproductive sites, and how they are maintained once they reach this destination. Animal studies have suggested that the rules for selection and maintenance of these cells, in terms of their requirement for MHC and their education within the thymus, may be distinct from those governing either peripheral immune cells or cells within other mucosal sites, including the intestine (148). It appears the human reproductive tract displays similar characteristics—the immunophenotypes of immune cells populating the human reproductive tract are distinct from both the periphery and from other mucosal sites (149,150). The education of TCRγδ+ cells populating epithelial sites may occur outside the thymus and might involve mechanisms that substitute for or modify interaction with MHC (141,151). The development of MHC specificity among NK cells is presently being carefully dissected in animal models with the hope that these investigations will shed light on similar processes in humans and, more specifically, on the selection and maintenance characteristics of decidual NK cells (133,134,152,153).
It is becoming increasingly evident that the cells populating mucosal immune tissues select these sites through interactions between cell surface molecules on the immune cell (integrins) and cell surface molecules on the endothelial cells of blood vessels within the mucosal tissues (e.g., selectins). This cellular recruitment process, called homing, has been most thoroughly described for the intestine (154,155). Both murine and human reproductive tract tissues express these integrin or vascular ligand pairs (155–157). The extension of these findings to pregnancy maintenance will be useful (158,159). Solving the mechanisms of selection, education, and maintenance of reproductive tract immune effector cells is of paramount importance. Until we understand these vital processes in the normal state, we cannot define the effects that alterations will have on human disease nor can we develop therapeutic interventions.