PREGNANCY FAILURE IS ESTIMATED TO AFFECT APPROXIMATELY 50% OF CATTLE WITHIN THE FIRST MONTH OF PREGNANCY AND IS ONE OF THE GREATEST CONTRIBUTORS TO ECONOMIC LOSSES FOR U.S. CATTLE INDUSTRIES. BIDIRECTIONAL SIGNALING IS ESSENTIAL FOR PREGNANCY AND UTILIZES SECRETED FACTORS, OFTEN IMMUNE RELATED, BOTH FROM THE CONCEPTUS (THE EMBRYO AND EXTRAEMBRYONIC TISSUES) AND THE UTERUS.IN HUMANS AND MICE, MATERNAL UTERINE IMMUNE CELLS ARE REGULATORS OF PLACENTAL DEVELOPMENT.PREGNANCY ASSOCIATED GLYCOPROTEINS (PAGS) ARE A FAMILY OF PLACENTA SECRETED MOLECULES WHICH ARE DETECTABLE IN MATERNAL BLOOD DURING THE PERIOD OF PREGNANCY LOSS, AND CLEAR ASSOCIATIONS HAVE BEEN MADE BETWEEN REDUCED CONCENTRATIONS OF PAGS AND PREGNANCY FAILURE. THIS STUDY WILL TEST THE HYPOTHESISTHAT PREGNANCY AND PAGS SECRETED BY THE PLACENTA OF CATTLE MODULATEMATERNAL IMMUNE RESPONSIVENESS, PROMOTING TOLERANCE OF THE EMBRYO AND PLACENTA. IN THE FIRST STUDY, WE WILL INVESTIGATE HOW THE POPULATIONS AND MOLECULAR FUNCTIONS OF UTERINE RESIDENT IMMUNE CELLS CHANGE DURING THE PERIOD OFPREGNANCY WHEN THE PLACENTA BEGINS TO FIRMLY ATTACH TO THE UTERUS. FOR THE SECOND STUDY, WE WILL DETERMINE IF PAGS PROMOTE CONCEPTUS TOLERANCE BY MODULATING THE INNATE IMMUNE RESPONSE OF ENDOMETRIAL EPITHELIAL CELLS (AIM 2A) AND SECRETORY FUNCTIONS OF THE CORPUS LUTEUM (AIM 2B). WE EXPECT TO ESTABLISH A BASELINE OF CHANGES OCCURRING DURING PREGNANCY TO THE POPULATIONS AND MOLECULAR FUNCTIONS OFIMMUNE CELLS AT THE MATERNAL-PLACENTAL INTERFACE. WE ALSO EXPECT THAT PAGS WILL ALTER THE IMMUNE RESPONSE OF UTERINE AND OVARIAN CELLS, REVEALING PATHWAYS WHICH MAY BE MODIFIED FOLLOWING EXPOSURE TO PAGS. THIS RESEARCH WILL IDENTIFY THE IMMUNOMODULATORY FUNCTIONS OF PREGNANCY AND PAGS IN CATTLE DURING PLACENTAL ATTACHMENT, FILLING A CRITICAL GAP IN THE FUNDAMENTAL KNOWLEDGE. FURTHERMORE, THIS RESEARCH WILL PROVIDE INSIGHT INTO HOW ALTERATIONS TO MATERNAL UTERINE IMMUNE CELLS MAY POTENTIATE PREGNANCY FAILURE, OPENING THE DOOR FOR POSSIBLE INTERVENTION STRATEGIES TO REDUCE PREGNANCY LOSS.