MATERNAL REGULATION OF EARLY LIFE ORIGIN B CELLS - PROJECT SUMMARY/ABSTRACT IN EARLY LIFE, THE IMMUNE SYSTEM RAPIDLY DEVELOPS IN CLOSE INTERACTION WITH THE INTESTINAL MICROBIOME, A PROCESS INFLUENCED BY BREASTMILK. BREASTMILK CONTAINS IMMUNOMODULATORY FACTORS, INCLUDING MATERNAL ANTIBODIES (MATABS), THAT SUPPORT IMMUNE-MICROBIOME HOMEOSTASIS AND REDUCE THE RISK OF MUCOSAL, IMMUNE-MEDIATED, AND METABOLIC DISORDERS LATER IN LIFE, COMPARED TO FORMULA FED COUNTERPARTS. AMONG THESE BIOACTIVE FACTORS, MATABS PLAY AN ESSENTIAL ROLE IN SHAPING MICROBIOTA COMPOSITION, CONTROLLING MICROBIAL COLONIZATION, MODULATING GENE EXPRESSION, AND DIRECTING EARLY IMMUNE DEVELOPMENT. HOWEVER, HOW THE ABSENCE OF MATABS ALTERS THESE INTERACTIONS AND INFLUENCES LONG-TERM IMMUNITY REMAINS UNCLEAR. THIS PROJECT AIMS TO DEFINE HOW MATERNAL ANTIBODIES REGULATE NEONATAL ADAPTIVE IMMUNE-MICROBIOTA INTERACTIONS AND SHAPE DURABLE MUCOSAL B CELL IMMUNITY. PREVIOUS WORK IN MICE HAS SHOWN THAT NEONATES LACKING MATABS EXHIBIT INCREASED MUCOSAL, MICROBIOTA- DEPENDENT TFH AND ASSOCIATED GERMINAL CENTER (GC) B CELL RESPONSES DURING THE WEANING TRANSITION. PROPER REGULATION OF MUCOSAL TFH CELLS AND T-DEPENDENT (TD) ANTIBODY PRODUCTION IS ESSENTIAL FOR MAINTAINING GUT HOMEOSTASIS. DISRUPTIONS IN EARLY-LIFE IMMUNE-MICROBIOTA INTERACTIONS ARE INCREASINGLY LINKED TO LATER DEVELOPMENT OF IMMUNE-MEDIATED DISEASES. GENETIC FATE-MAPPING APPROACHES HAVE REVEALED THAT GC B CELLS ACTIVATED DURING THE WEANING PERIOD GIVE RISE TO ANTIBODY-SECRETING CELLS THAT PERSIST IN THE ADULT LAMINA PROPRIA, SUGGESTING DURABLE IMMUNOLOGICAL IMPRINTING DURING THIS CRITICAL WINDOW. TWO SPECIFIC AIMS WILL BE PURSUED: (1) TO IDENTIFY THE IMMUNE-ACTIVATING MICROBES THAT DRIVE DYSREGULATED ADAPTIVE IMMUNE RESPONSES IN THE ABSENCE OF MATABS, AND (2) TO CHARACTERIZE THE LONG-LIVED NEONATAL MUCOSAL B CELL RESPONSE DERIVED FROM EARLY-LIFE GC B CELLS. THE PROJECT WILL EMPLOY CUTTING EDGE FATE MAPPING TOOLS, INNOVATIVE TRANSGENIC MOUSE MODELS, ANTIBIOTIC DEPLETION, 16S RRNA SEQUENCING, MICROBIOTA FLOW CYTOMETRY, AND SINGLE-CELL TRANSCRIPTOMICS APPROACHES TO MAP THESE RESPONSES. ELUCIDATING HOW BREASTFEEDING SHAPES NEONATAL IMMUNE-MICROBIOTA INTERACTIONS AND LONG-TERM MUCOSAL IMMUNITY COULD BENEFIT INDIVIDUALS WHO ARE NOT EXCLUSIVELY BREASTFED FOR THE SIX-MONTHS OF AGE AS RECOMMENDED- A POPULATION ESTIMATED TO BE APPROXIMATELY TWO-THIRDS OF ALL INFANTS IN THE WORLD. ULTIMATELY, THESE INSIGHTS MAY INFORM THE DEVELOPMENT OF TARGETED INTERVENTION- SUCH AS PASSIVE IMMUNIZATION, VACCINES, OR ENRICHED FORMULAS- TO PROMOTE IMMUNE BALANCE IN NON-BREASTFED INFANTS, THEREBY REDUCING THE LONG-TERM BURDEN OF ALLERGIC, INFLAMMATORY, MUCOSAL, AND METABOLIC DISEASES ROOTED IN EARLY-LIFE IMMUNE DYSFUNCTION.