The Establishment of Lung Resident Self-Antigen-Specific CD4+ Tregs Following Acute Tissue injury

PROJECT SUMMARY Self-antigen-specific T cells prevalent within the adaptive immune system pose an ever-present threat to health. Accordingly, they are heavily regulated at steady-state by mechanisms of peripheral tolerance. Infections and inflammation, however, offer an opportunity for these cells to become activated and initiate autoimmunity. While characterizing the response of self-antigen-specific T cells during inflammation with the use of peptide:MHC class II tetramers in an experimental mouse model of lung injury, we recently provided direct evidence that the immune system generates a polarized response towards tolerance during inflammation through the selective expansion of endogenous self-antigen-specific Foxp3+ Tregs. Moreover, we have preliminary evidence that these self-antigen-specific Tregs remain enriched within the T cell repertoire for months after the injury. We hypothesize that the “experienced” self-antigen-specific Tregs expanded during acute lung damage develop into a long-lived tissue-resident population that limits recurrent injury. Characterizing the development of lung- resident self-antigen-specific Tregs following lung injury addresses the broader question of how the adaptive immune response reinforces tolerance towards self-antigens presented during inflammation. To investigate our hypothesis, we have improved upon our experimental mouse model to harbor greater frequencies of polyclonal lung self-antigen-specific Tregs that respond to tissue injury, generated new “barcoded” tetramers for large scale transcriptomic studies, and implemented a parabiosis approach to monitor trafficking of these Tregs. In Aim 1, we will study the population dynamics of self-antigen-specific Tregs and determine whether they establish tissue- residence in the lungs. In Aim 2, we will characterize the phenotype and the function of self-antigen-specific Tregs expanded in the context of prior lung injury promote tolerance in future lung disease. Understanding how “experienced” self-antigen-specific Tregs guard against future lung injury will provide new insights into the ability of self-antigen-specific T cell repertoire to prevent of autoimmunity. Dr. Daniel Shin will perform the work for this K08 proposal, sponsored by Boston Children’s Hospital, at the Center for Immunology and Inflammatory Diseases, a state-of-the-art multidisciplinary research center, at Massachusetts General Hospital under the mentorship of Drs. James Moon and Andrew Luster. With the guidance of his co-mentors, Dr. Shin has set forth a comprehensive career development plan that will provide new technical skills in mouse immunology, develop greater mastery of RNA transcriptomics, and hone academic and professional skills training. To accomplish these goals, he has also assembled an exceptional Training Advisory Committee composed of Drs. Medoff, Villani, Chatila, and Oettgen who will provide invaluable expertise and assistance in the fields of lung inflammation, systems biology, Treg biology, and career development. The goal of this K08 award is to equip Dr. Shin with the intellectual and technical foundation to become a successful independent, NIH-funded investigator with expertise in peripheral tolerance, tissue-resident Tregs, and the prevention of organ-specific autoimmunity.