Rist Melissa J, Hibbert Kelly M, Croft Nathan P, Smith Corey, Neller Michelle A, Burrows Jacqueline M, Miles John J, Purcell Anthony W, Rossjohn Jamie, Gras Stephanie, Burrows Scott R
QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia; School of Medicine, University of Queensland, Brisbane, Queensland 4072, Australia;
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia; and.
J Immunol. 2015 May 15;194(10):4668-75. doi: 10.4049/jimmunol.1500233. Epub 2015 Apr 8.
T cell cross-reactivity underpins the molecular mimicry hypothesis in which microbial peptides sharing structural features with host peptides stimulate T cells that cross-react with self-peptides, thereby initiating and/or perpetuating autoimmune disease. EBV represents a potentially important factor in the pathogenesis of several T cell-mediated autoimmune disorders, with molecular mimicry a likely mechanism. In this study, we describe a human self-peptide (DELEIKAY) that is a homolog of a highly immunogenic EBV T cell epitope (SELEIKRY) presented by HLA-B18:01. This self-peptide was shown to bind stably to HLA-B18:01, and peptide elution/mass spectrometric studies showed it is naturally presented by this HLA molecule on the surface of human cells. A significant proportion of CD8(+) T cells raised from some healthy individuals against this EBV epitope cross-reacted with the self-peptide. A diverse array of TCRs was expressed by the cross-reactive T cells, with variable functional avidity for the self-peptide, including some T cells that appeared to avoid autoreactivity by a narrow margin, with only 10-fold more of the self-peptide required for equivalent activation as compared with the EBV peptide. Structural studies revealed that the self-peptide-HLA-B18:01 complex is a structural mimic of the EBV peptide-HLA-B18:01 complex, and that the strong antiviral T cell response is primarily dependent on the alanine/arginine mismatch at position 7. To our knowledge, this is the first report confirming the natural presentation of a self-peptide cross-recognized in the context of self-HLA by EBV-reactive CD8(+) T cells. These results illustrate how aberrant immune responses and immunopathological diseases could be generated by EBV infection.
T细胞交叉反应性是分子模拟假说的基础，在该假说中，与宿主肽具有结构特征的微生物肽刺激与自身肽发生交叉反应的T细胞，从而引发和/或延续自身免疫性疾病。EB病毒是几种T细胞介导的自身免疫性疾病发病机制中一个潜在的重要因素，分子模拟可能是其机制。在本研究中，我们描述了一种人类自身肽（DELEIKAY），它是由HLA - B18:01呈递的高免疫原性EB病毒T细胞表位（SELEIKRY）的同源物。该自身肽被证明能稳定结合HLA - B18:01，肽洗脱/质谱研究表明它在人类细胞表面由该HLA分子天然呈递。一些健康个体中针对该EB病毒表位产生的相当一部分CD8(+) T细胞与该自身肽发生交叉反应。交叉反应性T细胞表达了多种TCR，对自身肽具有可变的功能亲和力，包括一些似乎仅以微弱优势避免自身反应性的T细胞，与EB病毒肽相比，同等激活所需的自身肽仅多10倍。结构研究表明，自身肽 - HLA - B18:01复合物是EB病毒肽 - HLA - B18:01复合物的结构模拟物，并且强烈的抗病毒T细胞反应主要依赖于第7位的丙氨酸/精氨酸错配。据我们所知，这是第一份证实EB病毒反应性CD8(+) T细胞在自身HLA背景下交叉识别的自身肽天然呈递的报告。这些结果说明了EB病毒感染如何引发异常免疫反应和免疫病理疾病。
