Decoding human T-cell allospecificity

解码人类 T 细胞同种异体特异性

基本信息

批准号：
10608513
负责人：
Brian M Baker
金额：
$ 26.48万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-11-08 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10608513
关键词：
Acute Adrenal Cortex Hormones Affect Alloantigen Allografting Antigen-Presenting Cells Area Autoimmunity Automobile Driving Back Binding Biological Biology Biopsy CD8-Positive T-Lymphocytes Calcineurin inhibitor Cells Cellular biology Clonal Expansion Clone Cells Complex Consensus Cytomegalovirus Data Disease End stage renal failure Epitopes Genes Goals Graft Rejection Homologous Gene Human Human Herpesvirus 4 Immunobiology Immunologics Immunosuppression Individual Infection Kidney Transplantation Knowledge Ligands Link Malignant Neoplasms Maps Mediating Memory Mixed Lymphocyte Culture Test Monitor Morbidity - disease rate Nature Pathway interactions Patients Peptide Library Peptide/MHC Complex Peptides Peripheral Blood Mononuclear Cell Persons Play Prevention Quality of life Regimen Role Specificity Surface T cell response T cell therapy T memory cell T-Cell Activation T-Cell Depletion T-Lymphocyte T-Lymphocyte Epitopes Testing Therapeutic immunosuppression Tissue Transplantation Tissues Toxic effect Transplant Recipients Transplantation Urine Viral Virus Virus Diseases Work allograft rejection candidate identification cross reactivity differential expression established cell line experimental study high reward high risk infection risk insight kidney allograft metaplastic cell transformation mortality novel therapeutics pharmacologic premature response screening success therapeutic target transcriptome transcriptomics

项目摘要

Summary CD8+ T cells are the main drivers of acute cellular rejection (ACR) of transplanted tissues. While T cells can recognize alloantigens directly (through direct responses to allo-HLA) as well as indirectly (through allopeptides bound to self-HLA), the major consensus is that direct recognition plays a major role in ACR. However, much is unknown about the biology of T cells responsible for direct ACR. For decades, alloreactive T cells have been viewed as either responding primarily to unique determinants on allo-HLA (HLA-centric responses), or to a plethora of non-self peptides presented by allo-HLA (peptide-centric). Recent data though has suggested that many alloreactive T cells are allospecific, responding to unique peptide/allo-MHC complexes present on the surface of allografts. Moreover, additional data suggests that alloreactive T cells may share reactivities with immunodominant viral epitopes and may in fact derive from pre-existing memory pools. While there is growing clarity around the structural features and immunological origins of alloreactive T cells, the lack of knowledge regarding the specificities of alloreactive T cells is a major reason for our limited biologic insight into T cell- mediated ACR. We are now poised to make a substantial breakthrough in this area and capitalize on it to better understand ACR and alloreactivity in general. In initial studies, using scRNA sequencing on biopsies and urine from several patients undergoing kidney transplant rejection, we found a remarkably and unexpectedly small number (~10-20/patient) of clonally expanded T cells with unique TCR CDR3 a/b sequences, and have confirmed their specificity towards the transplanted tissue. These expanded T cell clones persist for months in rejecting allografts, despite traditional anti-rejection therapy. The goal of this ambitious, high risk/high reward project is to identify the ligands recognized by alloreactive T cells within transplant biopsies, including both alloantigens and any cross-reactive viral epitopes and use this knowledge to begin decoding the immunobiology of ACR, identify possible therapeutic targets, and expand our understanding of the nature and origins of alloreactivity. Our specific hypotheses are that (i) the majority of clonally expanded allospecific TCRs recognize unique tissue restricted peptides presented by allo-HLA; (ii) many of these TCRs are also cross-reactive with viral epitopes presented by self-HLA; and (iii) identification of peptide targets will enable us to decode the transcriptomes of allospecific T cells in kidney allografts. Success in this multi-PI R21 proposal will pave the way for numerous, deeper, groundbreaking studies of alloreactivity, graft rejection, and novel therapeutic modulation of ACR.

概括 CD8+ T 细胞是移植组织急性细胞排斥 (ACR) 的主要驱动因素。虽然 T 细胞可以直接识别同种异体抗原（通过直接反应同种异体 HLA）以及间接识别同种异体抗原（通过同种肽）与自身 HLA 结合），主要共识是直接识别在 ACR 中起着重要作用。然而，很多是负责直接 ACR 的 T 细胞的生物学特性尚不清楚。几十年来，同种异体反应性 T 细胞被视为主要响应异基因 HLA 上的独特决定因素（以 HLA 为中心的响应），或由allo-HLA（以肽为中心）呈现的大量非自身肽。但最近的数据表明许多同种异体反应性 T 细胞是同种异体特异性的，对存在于 T 细胞上的独特肽/同种异体 MHC 复合物做出反应同种异体移植物的表面。此外，额外的数据表明同种异体反应性 T 细胞可能与免疫显性病毒表位，实际上可能源自预先存在的记忆池。虽然有增长同种反应性 T 细胞的结构特征和免疫学起源不清楚，缺乏知识关于同种异体反应性 T 细胞的特异性是我们对 T 细胞的生物学认识有限的一个主要原因介导的 ACR。我们现在准备在这一领域取得实质性突破，并利用它更好地利用它总体了解 ACR 和同种异体反应性。在初步研究中，使用 scRNA 测序对活检和尿液进行测序从几位接受肾移植排斥反应的患者中，我们发现了一个非常出乎意料的小具有独特 TCR CDR3 a/b 序列的克隆扩增 T 细胞数量（~10-20/患者），并且具有证实了它们对移植组织的特异性。这些扩增的 T 细胞克隆在体内持续数月尽管有传统的抗排斥治疗，但仍会排斥同种异体移植物。这一雄心勃勃、高风险/高回报的目标该项目旨在鉴定移植活检中同种异体反应性 T 细胞识别的配体，包括同种异体抗原和任何交叉反应的病毒表位，并利用这些知识开始解码免疫生物学 ACR 的研究，确定可能的治疗靶点，并扩大我们对 ACR 的性质和起源的理解同种异体反应性。我们的具体假设是 (i) 大多数克隆扩展的同种异体 TCR 识别由allo-HLA 呈递的独特组织限制性肽； (ii) 其中许多 TCR 还与以下物质发生交叉反应：由自身HLA 呈递的病毒表位； (iii) 肽靶标的识别将使我们能够解码同种异体肾移植物中同种异体特异性 T 细胞的转录组。这项多 PI R21 提案的成功将为我们铺平道路对同种异体反应性、移植物排斥和新型治疗调节进行了大量、更深入、开创性的研究 ACR 的。