Marilen Benner

CHAPTER 6 156 Just as eNK and dNK cells are distinct from pbNK cells, the mucosal NK cells of the gut that are continuously exposed to the gut microbiome are distinct from pbNK cells. This distinction is characterized by limited IFN- γ production and an absence of cytotoxic effector perforin, granzymes, FasL and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in mucosal NK cells of the gut (105). Of note, germ-free mice lacked these IL-22 + NKp46 + cells (106). Hence, the specialized intestinal NK cells might be the result of an adaptation to the microbiota-rich environment. It needs to be evaluated whether the reduced cytotoxic capacity of uNK cells (107) has any relation to the uterine microbiota. APCs, such as macrophages (M ɸ ) and dendritic cells (DCs), constitute 10-20% of uterine leukocytes, expressing major histocompatibility complex class II molecules (108, 109). Through integrating microbial, environmental, and self-derived stimuli, APCs are key to the successful initiation of an appropriate immune response (110, 111). Throughout the menstrual cycle, mature CD83 + DCs and CD68 + M ɸ increase, peaking in the late secretory phase (112). M ɸ are, together with NK cells, the main cytokine producers in the human endometrium (113). Through secreting leukemia inhibitory factor (LIF) and IL1B, M ɸ play a known role in the establishment of endometrial receptivity by increasing cell surface fucosylated structures, allowing trophectoderm attachment (87). Even more pronounced than seen for NK cells, monocytes of the heavily colonized gut mucosa are markedly different in phenotype and function compared to blood-derived monocytes. Even though they reside in close proximity to bacteria colonizing the intestinal lumen, the ability of the local macrophages to mount a pro-inflammatory response seems to be tuned down. Their expression of, for example, lipopolysaccharide (LPS)-binding protein CD14 receptor (114), CD89, implicated in IgA-enhanced phagocytosis is decreased (115). Also, various FC γ receptors (CD16, CD32, CD64), integrins (CD11a, CD11b, CD11c, CD18) and the IL-2 receptor CD25 are, amongst others, downregulated on intestinal macrophages. Their ability to produce cytokines (IL-1, IL-6, TNF α ) is diminished (116). It needs to be investigated whether this Smad-induced I κ B α expression and NF- κ B inactivation-mediated phenotype, termed “inflammation anergy”, is paralleled at the fetal-maternal interface (117). T cells represent the third largest fraction of immune cells found in human endometrium (118-120). Since, in the absence of pregnancy, T cells mostly reside in the deeper layers of the endometrium, their relation to fertility disorders more likely reflects a role in early placenta formation after implantation, rather than a contribution to the pre-implantation period. Experimental evidence on the functional importance of T cells in the WOI is scarce. It has been suggested that a switch in the ratio of Th1 and Th2 cells (Th1/Th2 paradigm) within the endometrium is needed to prepare for implantation, as a pronounced decrease in Th1 was accompanied by an increase in Th2 cells