Project Grant R01AI184482

GLYCAN REGULATION OF FETOMATERNAL TOLERANCE - PROJECT SUMMARY/ABSTRACT A CENTRAL QUESTION IN REPRODUCTIVE IMMUNOLOGY IS HOW THE FETUS AND PLACENTA AVOID BEING REJECTED BY THE MATERNAL IMMUNE SYSTEM. DESPITE THE SUBSTANTIAL PROGRESS MADE ON THIS QUESTION IN RECENT YEARS, MANY KEY KNOWLEDGE GAPS REMAIN. THESE GAPS NOT ONLY PREVENT US FROM LEVERAGING UNDERLYING MECHANISMS TO INDUCE ANTIGEN-SPECIFIC IMMUNE TOLERANCE IN THE CLINICAL ARENA, BUT ALSO LIMIT INVESTIGATION INTO THE PATHOGENESIS OF INTRAUTERINE GROWTH RESTRICTION, SPONTANEOUS ABORTION, PREECLAMPSIA, AND PRETERM LABOR, I.E., PREGNANCY COMPLICATIONS THAT MAY ALL INVOLVE ABERRANT ACTIVATION OF THE MATERNAL IMMUNE SYSTEM TO PLACENTAL ANTIGENS. RECENTLY, OUR LABORATORY HAS DESCRIBED KEY ROLES FOR B CELL-MEDIATED ANTIGEN PRESENTATION AND ANTIGEN GLYCOSYLATION IN SUPPRESSING IMMUNE RESPONSES TO PLACENTAL ANTIGENS IN MICE. SPECIFICALLY, WE FOUND THAT A SURROGATE MODEL ANTIGEN EXPRESSED BY TROPHOBLASTS (T-MOVA) IS PRESENTED TO MATERNAL CD4 T CELLS EXCLUSIVELY BY ANTIGEN-SPECIFIC B CELLS, AND THAT THESE B CELLS ARE SUPPRESSED THROUGH THE ACTIONS OF T-MOVA'S HEAVILY SIALYLATED N-LINKED GLYCANS, THUS IN TURN SUPPRESSING THE CD4 T CELLS. THIS MAJOR NEW LINE OF INVESTIGATION RAISES IMMEDIATE QUESTIONS THAT WE ADDRESS IN THIS PROPOSAL. SPECIFICALLY, AIM 1 WILL USE BOTH MOUSE (T-MOVA) AND HUMAN MODELS TO EVALUATE THE HYPOTHESIS THAT GLYCAN-SPECIFIC IGM NATURAL ANTIBODIES BIND TO ANTIGENS SHED FROM THE PLACENTA, ACTIVATING COMPLEMENT AND THUS CAUSING THE ANTIGENS TO ACCUMULATE ON FOLLICULAR DENDRITIC CELLS IN THE SPLEEN. THIS ACCUMULATION IN TURN ALLOWS THE ANTIGENS' GLYCANS TO SUPPRESS ANTIGEN-SPECIFIC B CELLS. SUBSTANTIATION OF THIS PATHWAY WOULD SUGGEST NEW WAYS TO CONCEPTUALIZE THE PATHOGENESIS OF HUMAN PREGNANCY COMPLICATIONS SUCH AS PREECLAMPSIA THAT ARE LINKED TO INCREASED ANTIBODY AND COMPLEMENT DEPOSITION ON TROPHOBLAST MEMBRANES. AIM 2 THEN SEEKS TO THE DETERMINE THE FEATURES OF TROPHOBLAST GLYCANS THAT IMPART THEM WITH IMMUNOSUPPRESSIVE PROPERTIES, WHICH, TOGETHER WITH AIM 1, WOULD INFORM HOW BEST TO HARNESS TROPHOBLAST GLYCOBIOLOGY FOR THERAPEUTIC PURPOSES. IT WILL EMPLOY A VARIETY OF TECHNIQUES INCLUDING MASS SPECTROMETRY TO DEFINE THE STRUCTURES OF T-MOVA'S GLYCANS, AND WILL FINGERPRINT THE GLYCANS THAT DECORATE HUMAN SYNCYTIOTROPHOBLAST BRUSH BORDER MEMBRANE PROTEINS BATHED IN MATERNAL BLOOD. LASTLY, AIM 3 WILL ADDRESS THE BEHAVIOR OF THE TISSUE RESIDENT MEMORY T CELLS THAT POPULATE THE DECIDUA. THESE CELLS ARE POSITIONED TO DEFEND AGAINST CONGENITAL INFECTION BUT ALSO POSE POTENTIAL DIRECT THREATS TO FETAL SURVIVAL. USING MOUSE MODELS, IT WILL DETERMINE THE RESPONSIVENESS OF THE CELLS TO TROPHOBLAST ANTIGENS, AS WELL AS WHETHER THEY ARE SUPPRESSED BY TROPHOBLAST ANTIGEN-ASSOCIATED GLYCANS, LIKE B AND T CELLS ARE SYSTEMICALLY. TOGETHER, WE EXPECT THIS WORK TO HAVE A MAJOR IMPACT ON THE FIELD AS IT BEGINS TO CONNECT THE DISCOVERY THAT GLYCANS PLAY A CENTRAL ROLE IN FETOMATERNAL TOLERANCE WITH OTHER CRITICAL QUESTIONS IN REPRODUCTIVE IMMUNOLOGY AND OBSTETRICS. THE WORK WILL ALSO FURTHER A SECOND LONG-TERM GOAL OF THE FETOMATERNAL TOLERANCE FIELD, NAMELY, TO FOSTER APPLICATION OF UNDERLYING MECHANISMS TO IMMUNE TOLERANCE INDUCTION IN THE CLINICAL ARENA.