DETERMINANTS OF B CELL RESIDENCY IN ALLERGIC LUNGS - PROJECT SUMMARY/ABSTRACT ALLERGIC ASTHMA IS A CHRONIC INFLAMMATORY AIRWAY DISEASE WHERE THE AIRWAY CONSTRICTS IN RESPONSE TO INHALED ALLERGENS. A MAJOR DRIVER OF THE PATHOLOGY IS ALLERGEN-SPECIFIC IGE ANTIBODIES. IN CONTRAST TO THE CONVENTIONAL BELIEF THAT IGE CIRCULATES THROUGH THE BLOOD TO ENTER THE LUNGS, OUR LAB RECENTLY SHOWED THAT IN A MOUSE MODEL OF AIRWAY HYPERSENSITIVITY, INHALED ALLERGENS INDUCE THE FORMATION OF LYMPHOID STRUCTURES AND LUNG-RESIDENT MEMORY B CELLS (MBCS), WHICH MAINTAIN THE LONG-TERM LOCAL IGE RESPONSE AT THE RESPIRATORY MUCOSA. HOWEVER, THE MECHANISMS THAT RECRUIT AND RETAIN MBCS IN THE ALLERGIC LUNG ARE UNKNOWN. STROMAL CELLS ARE KNOWN TO ORGANIZE AND MAINTAIN LYMPHOID ORGANS. IN LUNG INFECTIONS, LUNG STROMAL CELLS CAN ALSO BE ACTIVATED TO FUNCTION AS LYMPHOID ORGANIZERS. THUS, I ASKED IF THE LUNG STROMA IN ALLERGIC INFLAMMATION CAN SUPPORT MBC RESIDENCY. I PERFORMED SINGLE CELL RNA- SEQ EXPERIMENTS ON STROMAL CELLS FROM ALLERGIC LUNGS AND BIOINFORMATICALLY PAIRED THE STROMAL DATASET WITH LUNG MBC DATASETS TO IDENTIFY POTENTIAL LIGAND-RECEPTOR PAIRS. THIS ANALYSIS PREDICTED MULTIPLE INTERACTIONS BETWEEN MBCS AND FIBROBLASTS VIA EXTRACELLULAR MATRIX PROTEINS AND SURVIVAL FACTORS. ADDITIONALLY, SINGLE-CELL RNA SEQ ANALYSIS AND IMMUNOPROFILING ON LUNG MBCS REVEALED UPREGULATION OF ADHESION MOLECULES THAT MEDIATE ENTRY INTO INFLAMED TISSUES. THEREFORE, I HYPOTHESIZE THAT ADHESION MOLECULES FACILITATE MBC ENTRY INTO INFLAMED LUNGS WHERE FIBROBLASTS CREATE ECM-RICH NICHES TO SUPPORT MBC RETENTION. IN THIS PROPOSAL, I WILL INTERROGATE THE STROMAL AND IMMUNE CELL INTERACTIONS THAT MEDIATE THE RECRUITMENT AND RETENTION OF B CELLS IN THE ALLERGIC AIRWAYS. SPECIFICALLY, IN AIM 1, I WILL CHARACTERIZE THE CELLULAR COMPOSITION AND KEY STROMAL-MBC INTERACTIONS OCCURRING WITHIN LUNG LYMPHOID TISSUE USING SPATIAL TRANSCRIPTOMICS, FLUORESCENCE MICROSCOPY, EX VIVO CO-CULTURE ASSAYS, AND FIBROBLAST ADOPTIVE TRANSFERS. IN AIM 2, I WILL DETERMINE THE B CELL-INTRINSIC FACTORS THAT LEAD TO THEIR RESIDENCY IN THE LUNG THROUGH IN VIVO BLOCKADE EXPERIMENTS AND ADOPTIVE TRANSFERS. THE GOAL OF THIS FELLOWSHIP PROPOSAL IS TO IDENTIFY THE KEY INTERACTIONS THAT FACILITATE LUNG RESIDENCY OF MEMORY B CELLS IN ALLERGIC ASTHMA AND THUS, NEW TARGETS TO DISRUPT THE LOCAL PRODUCTION OF ALLERGEN-SPECIFIC IGE. ADDITIONALLY, THIS FELLOWSHIP WILL PROVIDE ME WITH THE TRAINING TO DEVELOP INTO AN INDEPENDENT SCIENTIST WITH THE NECESSARY SKILLS AND CRITICAL THINKING TO ADVANCE IN THE FIELD OF IMMUNOLOGY.