Effect of Ag-specific CD8+ T cell deletion on diabetogenesis in the NOD mouse

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DESCRIPTION (provided by applicant): Candidate: The investigator is a veterinary oncologist at NCSU-CVM, with a PhD in immunology. His immediate goals are to continue a recently-begun project examining the use of cytotoxic class I tetramers to eliminate pathogenic CD8+ T cells in type 1 diabetes (T1D). His long-term goals are to direct an externally-funded, basic research laboratory investigating the regulation of T cell immunity, which will hopefully lead to the development of innovative therapeutic strategies for autoimmunity and cancer. For several years the candidate has worked collaboratively in the laboratory of his sponsor, Dr. Jeffrey Frelinger, Kenan Professor of Immunology at UNC-CH. Under the proposed 4-year award, the candidate will transition his research project from UNC-CH into a laboratory that he will establish in a new facility at NCSU. To assist in this transition, and to provide guidance on research, scholarly productivity, and career development, the candidate will have two co-sponsors: Dr. Hauck (NCSU), an oncologist and former mentor; and Dr. Tisch (UNC-CH), an expert on T1D and a co-investigator on the candidate's current project. Planned and informal meetings with mentors, as well as other specialized training, will assist in the candidate's growth as an independent scientist. Environment: The sponsor has an impressive track record of scientific productivity, funding, and training^ clinician-scientists. The laboratory and core facility resources at both institutions are well-suited to completing the proposed work, and the intellectual climate is excellent. The candidate's department is committed to his career development as a scientist and supports the time requirements necessary for research. Research project: Studies in the NOD model of T1D implicate CD8+ T cells in diabetogenesis, and a dominant islet-infiltrating clonotype that recognizes IGRP206-214 has been identified. Our preliminary data show that these T cells can be selectively deleted in vivo by a cytotoxic high-avidity cognate tetramer; however, this tolerogenic strategy may ultimately fail if pathogenic T cells re-expand to fill the clonotype "space" created by deletion. We propose to evaluate strategies for preferentially expanding non-pathogenic T cells within this vacancy, and if successful, investigate the effects of this dual strategy on the functional composition of islet T cell populations. Relevance: This research will help to determine the role of killer T cells in juvenile diabetes, and potentially characterize a new strategy for treating this disease.