MHC and Peptide Specificity Underpin CD8+ T cell Direct Alloresponse.

IF 8.9 2区 医学 Q1 SURGERY American Journal of Transplantation Pub Date : 2024-10-19 DOI:10.1016/j.ajt.2024.10.011
Weiwen Zhang, Fernanda M Roversi, Anna B Morris, Kristina Ortiz, Grace Zhou, Annette Hadley, Xueqiong Zhang, Juliete A F Silva, Cynthia P Breeden, Zhuldyz Zhanzak, Haydn T Kissick, Christian P Larsen
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Abstract

The direct alloresponse, pivotal in transplant rejection, occurs when recipient T cells recognize intact allogeneic peptide-MHC complexes. Despite extensive research, our understanding of alloreactive CD8+ T cells against an individual MHC allele in humans remains limited, especially their precursor frequency, MHC specificity, and peptide specificity. By utilizing K562 cell-based artificial antigen-presenting cells (aAPCs) expressing HLA-A*01:01, HLA-A*02:01, or HLA-A*03:01, we determined that the precursor frequency of alloreactive CD8+ T cells against a single MHC allele ranges from 0.1% to 0.5%. Further, these cells exhibited MHC-specificity regarding proliferation, activation, IFN-γ secretion, and cytolytic ability, with limited cross-reactivity towards non-targeted MHC alleles. Focusing on anti-A2 alloreactive CD8+ T cells, we developed a peptide-exchangeable aAPC that displays selected peptides on HLA-A*02:01. From a set of 95 computationally curated A2-restricted peptides most abundant in renal tubular cells, we identified two immunogenic kidney peptides across multiple donors. Overall, our findings significantly enhance the understanding of direct alloresponse and provide a toolkit for future mechanistic studies and reproducible patient monitoring.

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MHC 和多肽特异性是 CD8+ T 细胞直接异反应的基础。
当受体 T 细胞识别到完整的异体肽-MHC 复合物时,就会产生直接异体反应,这种反应在移植排斥中起着关键作用。尽管进行了大量研究,但我们对人类针对单个 MHC 等位基因的异源反应 CD8+ T 细胞的了解仍然有限,尤其是它们的前体频率、MHC 特异性和肽特异性。通过使用表达 HLA-A*01:01、HLA-A*02:01 或 HLA-A*03:01 的基于 K562 细胞的人工抗原递呈细胞(aAPCs),我们确定了针对单个 MHC 等位基因的异源性 CD8+ T 细胞的前体频率为 0.1% 到 0.5%。此外,这些细胞在增殖、活化、IFN-γ分泌和细胞溶解能力方面表现出MHC特异性,对非目标MHC等位基因的交叉反应有限。我们以抗 A2 特异反应的 CD8+ T 细胞为重点,开发了一种可显示 HLA-A*02:01 上选定肽的肽交换型 aAPC。我们从肾小管细胞中最丰富的一组 95 个经过计算筛选的 A2 限制肽中,在多个供体中发现了两种免疫原性肾肽。总之,我们的研究结果大大提高了人们对直接异体反应的认识,并为未来的机理研究和可重复的患者监测提供了一个工具包。
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来源期刊
CiteScore
18.70
自引率
4.50%
发文量
346
审稿时长
26 days
期刊介绍: The American Journal of Transplantation is a leading journal in the field of transplantation. It serves as a forum for debate and reassessment, an agent of change, and a major platform for promoting understanding, improving results, and advancing science. Published monthly, it provides an essential resource for researchers and clinicians worldwide. The journal publishes original articles, case reports, invited reviews, letters to the editor, critical reviews, news features, consensus documents, and guidelines over 12 issues a year. It covers all major subject areas in transplantation, including thoracic (heart, lung), abdominal (kidney, liver, pancreas, islets), tissue and stem cell transplantation, organ and tissue donation and preservation, tissue injury, repair, inflammation, and aging, histocompatibility, drugs and pharmacology, graft survival, and prevention of graft dysfunction and failure. It also explores ethical and social issues in the field.
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