Decoding human T-cell allospecificity

解码人类 T 细胞同种异体特异性

• 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
• 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

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.

总结 CD 8 + T细胞是移植组织的急性细胞排斥（ACR）的主要驱动力。虽然T细胞可以 直接（通过对同种异体HLA的直接应答）以及间接（通过同种异体肽）识别同种异体抗原 与自身HLA结合），主要共识是直接识别在ACR中起主要作用。然而， 对直接ACR的T细胞生物学尚不清楚。几十年来，同种异体反应性T细胞一直是 被视为主要响应于异基因HLA上的独特决定因素（HLA中心反应），或响应于 由同种异体HLA呈递的过多非自身肽（肽中心）。但最近的数据显示， 许多同种异体反应性T细胞是同种异体特异性的，对存在于细胞表面的独特肽/同种异体-MHC复合物产生应答。 同种异体移植物表面。此外，额外的数据表明，同种异体反应性T细胞可能与同种异体反应性T细胞具有相同的反应性。 免疫显性病毒表位，并且实际上可能来源于预先存在的记忆库。虽然有越来越多的 围绕同种异体反应性T细胞的结构特征和免疫起源的清晰度，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细胞生物学认识有限的主要原因， 介导的ACR。我们现在准备在这一领域取得实质性突破，并利用这一突破， 了解ACR和同种异体反应性。在最初的研究中，对活检和尿液进行scRNA测序， 从几个接受肾移植排斥反应的患者中，我们发现了一个非常小的，出乎意料的 具有独特TCR CDR 3 a/B序列的克隆扩增T细胞数量（约10-20/患者）， 证实了它们对移植组织的特异性。这些扩增的T细胞克隆持续数月， 排斥同种异体移植物，尽管传统的抗排斥治疗。这个雄心勃勃、高风险/高回报的目标 一个项目是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性病毒表位，并使用这些知识来开始解码免疫生物学 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）大多数克隆扩增的同种异体特异性TCR识别 由allo-HLA呈递的独特的组织限制性肽;（ii）这些TCR中的许多也与 由自身HLA呈递的病毒表位;和（iii）肽靶的鉴定将使我们能够解码 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 对于同种异体反应性、移植排斥和新型治疗调节的众多、更深入、突破性研究 的ACR。