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

描述(申请人提供)：应聘者：调查者是NCSU-CVM的兽医肿瘤学家，拥有免疫学博士学位。他的近期目标是继续最近开始的一个项目，检查使用细胞毒I类四聚体来消除1型糖尿病(T1D)中致病的CD8 T细胞。他的长期目标是领导一个外部资助的基础研究实验室，研究T细胞免疫的调节，这将有望导致自身免疫和癌症的创新治疗策略的开发。几年来，这位候选人一直在他的赞助商、北卡罗来纳大学免疫学凯南教授杰弗里·弗雷林格博士的实验室合作。根据拟议的为期4年的奖励，候选人将把他的研究项目从北卡罗来纳大学转到他将在NCSU的一个新设施中建立的实验室。为了帮助这一过渡，并在研究、学术生产力和职业发展方面提供指导，候选人将有两个共同赞助人：Hauck博士(NCSU)，肿瘤学家和前导师；Tisch博士(北卡罗来纳大学-CH)，T1D专家，候选人当前项目的联合研究员。与导师的计划和非正式会议，以及其他专业培训，将有助于候选人作为一名独立科学家的成长。环境：赞助商在科学生产力、资金和临床医生-科学家培训方面有着令人印象深刻的记录。这两个机构的实验室和核心设施资源都非常适合完成拟议的工作，而且智力氛围也很好。应聘者所在的部门致力于他作为一名科学家的职业发展，并支持必要的研究时间要求。研究项目：在T1D的NOD模型中的研究表明CD8 T细胞参与了糖尿病的发生，并且已经确定了识别IGRP206-214的显性胰岛浸润性克隆型。我们的初步数据显示，这些T细胞可以在体内被细胞毒的高亲和力同源四聚体选择性删除；然而，如果致病T细胞重新扩张以填补因缺失而产生的克隆型“空间”，这种耐受策略可能最终失败。我们建议评估在这一空缺中优先扩增非致病T细胞的策略，如果成功，则调查这种双重策略对胰岛T细胞群体功能组成的影响。相关性：这项研究将有助于确定杀伤性T细胞在青少年糖尿病中的作用，并有可能确定治疗这种疾病的新策略。

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.