Investigation of the Molecular Basis of T Cell Alloreactivity

描述（由申请人提供）：申请人是一名致力于研究临床相关问题的内科科学家，目标是发展成为一名独立研究者。通过免疫学和临床病理学的培训，重点是移植和临床组织相容性，候选人已经发展了必要的临床专业知识，以识别临床相关和科学上重要的问题，并将基础科学发现转化为临床医学。有了这些技能，这位候选人在圣路易斯华盛顿大学导师Paul M. Allen的帮助下，开展了一项研究项目，以解决同种异体移植的基本障碍，即T细胞对同种异体主要组织相容性复合体（MHC）分子的强烈原发性同种异体反应。虽然人们早就认识到MHC的广泛多态性以及MHC通过T细胞受体（TCR）激活T细胞的直接作用使MHC成为移植的主要抗原屏障，但TCR和同种异体MHC之间的分子相互作用仍然是一个谜。同种异体反应性在T细胞识别抗原的基础认识以及临床同种异体移植中都是重要的。申请人和导师假设，介导移植物抗宿主病（GvHD）的同种反应性T细胞库（一种与临床高度相关的同种反应性表现）通过自然表达双TCR的T细胞而扩大，并且与GvHD相关的TCR库在很大程度上受到CDR3组成的影响，CDR3对所提肽抗原的特异性或多特异性识别至关重要。为了解决这些问题，申请人建议继续研究TCR曲目对GvHD的影响；申请人建议将证明高异位反应性双TCR T细胞参与GvHD的初步结果转化为人类模型，包括用于诊断测试开发的临床可行性研究。此外，申请人建议检查介导GvHD的T细胞库的广度，以确定TCR库易导致同种异体反应性的分子决定因素，以及随后的功能研究，以确定TCR与同种异体MHC和呈递肽的关键分子相互作用。总之，这些研究将提高对定义导致GvHD的同种异体反应性T细胞反应的分子相互作用的理解，使进一步的研究和合理设计改进的诊断、免疫抑制剂和供体匹配策略成为可能。在此申请中提出的工作，结合艾伦博士的指导和华盛顿大学病理和免疫学系学术界的支持，将使申请人发展成为一名独立的研究者医师科学家。同种反应性T细胞受体库的分子定义

DESCRIPTION (provided by applicant): The applicant is a physician-scientist dedicated to investigating clinically-relevant questions with the goal of developing a career as an independent investigator. Through training in immunology and clinical pathology focusing on transplantation and clinical histocompatibility the candidate has developed clinical expertise necessary for discerning clinically-relevant and scientifically important questions and translating basic science findings into clinical medicine. With these skills, the candidate, with help from mentor Paul M. Allen at Washington University in St. Louis, has developed a research project to address the fundamental barrier to allogeneic transplantation, the strong primary alloreactive response of T cells to allogeneic major histocompatibility complex (MHC) molecules. While it has long been recognized that the wide array of polymorphisms in MHC in combination with the direct role of MHC in activation of T cells through the T cell receptor (TCR) makes MHC the primary antigenic barrier to transplantation, the molecular interactions between TCR and allogeneic MHC defining alloreactivity remain enigmatic. Alloreactivity is important both in fundamental understanding of T cell recognition of antigen, as well as in clinical allogeneic transplantation. The applicant and mentor hypothesize that the repertoire of alloreactive T cells mediating graft vs. host disease (GvHD), a highly clinically-relevant manifestation of alloreactivity, is expanded by T cells naturally expressing dual TCRs and that the TCR repertoire involved in GvHD is greatly influenced by CDR3 composition which is critical for specific or polyspecific recognition of presented peptide antigens. To address these questions, the applicant proposes research that continues investigation of the influence of the TCR repertoire in GvHD; the applicant proposes to translate preliminary results demonstrating the participation of highly alloreactive dual TCR T cells in GvHD to human models, including clinical feasibility studies for diagnostic test development. Additionally, the applicant proposes examining the breadth of the repertoire of T cells mediating GvHD, to identify molecular determinants of the TCR repertoire predisposing alloreactivity, and subsequent functional studies to determine critical molecular interactions of the TCR with allogeneic MHC and presented peptides. Together, these studies will improve understanding of molecular interactions defining the alloreactive T cell response responsible for GvHD, enabling further investigation and rational design of improved diagnostics, immunosuppressive agents, and donor matching strategies. The work proposed in this application, in combination with the mentorship of Dr. Allen and the support of the academic community at the Department of Pathology and Immunology at Washington University will enable the applicant to develop into an independent investigator physician scientist. Molecular Definition of the Alloreactive T Cell Receptor Repertoire Project Narrative Alloreactivity, T cell recognition of allogeneic MHC, is an important area of investigation, both for understanding T cell biology, as well as in successful clinical transplantation; T cell recognition of allogeneic MHC is the primary barrier to successful clinical allogeneic transplantation, though the molecular interactions of TCR with allogeneic MHC and presented peptides are not well defined. This project aims to advance understanding of the molecular features of these interactions, enabling subsequent advances in solid organ and hematopoietic stem cell transplantation.