The immune system in the human endometrium maintains the delicate balance between defense against foreign pathogens and tolerance allowing for the implantation and development of a semi-allogeneic conceptus. Uterine NK cells which may comprise up to 70% of the leukocyte population have been implicated as key players in maintaining this balance. NKG2D is an activating receptor expressed on human NK cells, γδ T cells and CD8 T cells. NKG2D ligands are known to be sensors of cellular “stress”. This study examined regulatory immune interactions in the human female reproductive tract (FRT) mediated via NKG2D-ligand association; under physiological and pathological conditions.

Our studies revealed the presence of NKG2D ligands throughout the human FRT. MICA was predominantly expressed in all the tissues. MICA protein expression detected on epithelial cells in tissues of the human FRT changed from a localized to generalized pattern descending from the upper to the lower FRT tissues, where exposure to commensals was greater. Greater MICA expression was also observed in immunohistochemical analysis of endometria from patients in the secretory phase of the menstrual cycle. Since the endometrium undergoes cyclical changes regulated by sex hormones, we investigated whether sex hormones directly regulate expression of NKG2D ligands in the human uterus. Estradiol increased MICA expression on uterine epithelial cells; regulation was estrogen receptor-dependent. Thus, estrogens regulate expression of MICA. These data suggest hormonal regulation of innate immunity and NKG2Dmediated recognition in other tissues and diseases where estrogen may be involved.

Uterine NK cells, uterine macrophages and uterine epithelial cells are present in significant numbers and in close proximity in the endometrium, yet the ways in which these primary cells cooperatively respond to infectious challenge are poorly understood. This study shows that upon TLR3 stimulation, human uNK cells interact with autologous uterine macrophages and epithelial cells to produce IFN-γ, in an NKG2D-dependent manner. NK cells do not react in isolation to pathogenic stimuli. These studies demonstrate that the NKG2D-MICA interaction is an important molecular mechanism that is involved in regulation of endometrial immune network. The data support the hypothesis that expression of NKG2D ligands is regulated in the human female reproductive tract and the immune cells expressing them interact reciprocally with other cells expressing NKG2D. Such collaborative action helps in maintenance of the required immune paradox.