Maternal immune changes during bovine pregnancy: A focus on the endometrial macrophage

The presence of conceptus alloantigens necessitates changes in maternal immune function. Here, using the cow as a model, we evaluated these changes. In early pregnancy, there was no effect of pregnancy status on number of cells positive for CD8, CD4, gammadeltaT cell receptor, or the monocyte marker CD68 in the peripheral blood mononuclear cell (PBMC) population compared to nonpregnant cows. However, there was an increase in the proportion of CD4 + cells that were positive for CD25 at day 33-34 of pregnancy in the cow. Periparturient cows had an increased percent of PBMC that were gammadelta T cells and that co-expressed CD4+CD25+. Moreover, there was a tendency for a lower percentage of circulating CD68+ cells. The increase in cells co-expressing CD4+CD25 + reflects an increase in the proportion of cells that were CD4 + rather than in the proportion of CD4+ cells that also were CD25+. In the endometrium, there were increased numbers of CD68+ cells in interplacentomal regions in pregnant cows as compared to non-pregnant cows and these cells were also abundant in caruncular septa of the placentome. However, CD68+ cells were not present in the in fetal villi of the placentomes or in the interplacentomal chorion. Regardless of location, the majority of CD68+ cells also expressed CD14, another monocyte macrophage marker. In the interplacentomal endometrium, CD68+ cells were present in deeper areas of the endometrial stroma co-expressed CD11b+, but not in shallow region. In caruncular septa of the placentome, CD68+ cells were negative for CD11b. CD68+ cells in the interplacentomal endometrium were negative for MHC class II while most CD68+ cells in caruncular septa were positive for MHC class II. Macrophages co-expressing CD68+CD14 + present in the stroma of the interplacentomal endometrium and in the caruncular septa of the placentome were regionally differentiated with regards to expression of CD11b and MHC class II. Moreover the macrophages present in the pregnant endometrium are regionally differentiated perhaps as a result of the different maternal and fetal interaction between the interplacentomal and placentome region in the cow. Transcriptomal analysis of endometrial CD14 + cells showed that these cells express genes characteristic of macrophages; the endometrial macrophages overexpressed genes related to alternative (M2) activation pathway. Gene ontology analysis comparing differentially-regulated genes between endometrium and blood CD14+ cells showed an enrichment of ontologies related to proteolysis activity which suggests a tissue remodeling role for the endometrial macrophages. Despite differences in the types of placentation between human and bovine, many genes preferentially regulated in decidual macrophages were also differentially regulated between blood and endometrial macrophage in the cow. Around 17% of the genes found to be differentially expressed between decidual and blood human monocytes were also differentially expressed in the same direction for the cow. Presence of macrophages in the endometrium during late pregnancy suggests a role for these cells in parturition, expulsion of fetal membranes, and the process of uterine involution. Better understanding of the complex role of the endometrial macrophages may help researchers develop new practical techniques to positively affect the ability of cows to establish pregnancy following parturition.