Project Grant K99AI184587

ROLE OF THYMIC B CELLS IN IMMUNE TOLERANCE - PROJECT SUMMARY/ABSTRACT GENERATION OF A FUNCTIONAL ADAPTIVE IMMUNE RESPONSE RELIES ON THE COLLABORATION OF THE CELLULAR (T CELL) AND HUMORAL (B CELL) COMPARTMENTS. T FOLLICULAR HELPER (TFH) CELLS PROVIDE ESSENTIAL HELP TO B CELLS TO UNDERGO ISOTYPE CLASS-SWITCH RECOMBINATION AND GENERATE HIGH-AFFINITY ANTIBODY THROUGH SOMATIC HYPERMUTATION. FOLLICULAR REGULATORY T (TFR) CELLS HAVE BEEN IMPLICATED IN CONTROLLING THIS PROCESS AS THEY HAVE BEEN SHOWN TO BE CRITICAL IN REGULATING GERMINAL CENTER B CELL RESPONSES AND PREVENT AUTOANTIBODY FORMATION. HOWEVER, HOW THESE TFR CELLS DEVELOP IS UNKNOWN. B CELLS UNDERGO A UNIQUE TYPE-III INTERFERON DEPENDENT AND ISOTYPE CLASS- SWITCHING PROCESS IN THE THYMUS, THE LOCATION OF T CELL DEVELOPMENT, AND INDUCE CLONAL DELETION AND TREG CELL SELECTION. DEVELOPING TREG CELLS THAT DEPEND ON LICENSED THYMIC B CELL ANTIGENS MAY ALSO INTERACT WITH ACTIVATED B CELLS IN THE PERIPHERY AND TAKE ON A TFR PHENOTYPE. THUS, TREG CELLS SELECTED BY THYMIC B CELLS MAY BECOME TFR CELLS IN THE PERIPHERY AND HELP TO REDUCE THE RISK AUTOANTIBODY GENERATION. THE OBJECTIVE OF THIS WORK IS TO UNDERSTAND WHAT ROLE LICENSED THYMIC B CELLS PLAY IN T CELL TOLERANCE. IN THIS PROPOSAL WE IDENTIFIED T CELL RECEPTORS THAT GENERATE TFR CELLS WHEN EXPRESSED BY DEVELOPING T CELLS, PROPOSE TO STUDY THE REQUIREMENTS OF THESE TCRS FOR SELECTION AS WELL AS EXPLORE FURTHER FUNCTIONAL CONSEQUENCES WHEN THYMIC B CELLS ARE ABSENT. OUR CENTRAL HYPOTHESIS IS THAT TYPE-III INTERFERON DRIVES THYMIC B CELL LICENSING, RESULTING IN THE PRESENTATION OF B CELL ACTIVATION INDUCED SELF-PEPTIDES, THEREBY SUPPORTING THE DEVELOPMENT OF TREG CELLS THAT BECOME TFR CELLS AND REGULATE HUMORAL IMMUNE RESPONSES. THROUGH THIS WORK WE HOPE TO GENERATE A MECHANISTIC UNDERSTANDING OF THE IMPACT OF THYMIC B CELL ACTIVATION ON IMMUNE TOLERANCE. THESE FINDINGS WILL HAVE THE POTENTIAL TO REVEAL NEW PATHWAYS REGULATING ADAPTIVE IMMUNE RESPONSES AND HAVE IMPLICATIONS IN OUR UNDERSTANDING OF AUTOIMMUNE DISEASES LIKE SYSTEMIC LUPUS ERYTHEMATOUS OR RHEUMATOID ARTHRITIS, DISEASES WHERE PATHOGENIC AUTOREACTIVE ANTIBODIES MEDIATE DISEASE. I AM APPLYING FOR THIS K99/R00 AS AN INSTRUCTOR IN LABORATORY MEDICINE AND PATHOLOGY DEPARTMENT WITH SUBSPECIALTY TRAINING IN MOLECULAR PATHOLOGY. MY LONG-TERM CAREER GOALS ARE TO SUPPORT FOR THE CLINICAL DIAGNOSIS OF AUTOIMMUNITY AND INBORN ERRORS OF IMMUNITY AND TO LEAD AN R01 FUNDED RESEARCH PROGRAM THAT INVESTIGATES CENTRAL TOLERANCE AND IMMUNODEFICIENCY.