HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis.
HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis.
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HLA-DR 15分子共同塑造多发性硬化症的自身反应性T细胞库
DOI：
10.1016/j.cell.2020.09.054
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发表时间：
2020-11-25
期刊：
影响因子：
64.5
通讯作者：
Martin R
中科院分区：
文献类型：
--
作者：
Wang J;Jelcic I;Mühlenbruch L;Haunerdinger V;Toussaint NC;Zhao Y;Cruciani C;Faigle W;Naghavian R;Foege M;Binder TMC;Eiermann T;Opitz L;Fuentes-Font L;Reynolds R;Kwok WW;Nguyen JT;Lee JH;Lutterotti A;Münz C;Rammensee HG;Hauri-Hohl M;Sospedra M;Stevanovic S;Martin R
HLA-DR 15单倍型是多发性硬化症（MS）最强的遗传危险因素，但我们对其如何导致MS的理解有限。由于自身反应性CD 4 + T细胞和B细胞作为抗原呈递细胞参与MS发病机制，我们表征了人类原代B细胞和单核细胞、胸腺和MS脑组织的两种HLA-DR 15同种异型物DR 2a和DR 2B b的免疫肽段。来自HLA-DR分子，特别是来自DR 2 a和DR 2 B自身的自身肽在B细胞和胸腺抗原呈递细胞上是丰富的。此外，我们鉴定了自身反应性CD 4 + T细胞克隆，其可以与HLA-DR衍生的自身肽（HLA-DR-SP）、来自MS相关外源因子（Epstein-Barr病毒和嗜粘蛋白阿克曼氏菌）的肽以及由DR 2a和DR 2b呈递的自身抗原交叉反应。因此，在本发明中，两种HLA-DR 15同种异型体通过充当抗原呈递结构和表位来源以及通过将相同的外源肽和自身抗原呈递给MS中的自身反应性CD 4 + T细胞，共同形成自身反应性T细胞库。HLA-DR 15在B细胞上呈递丰富的HLA-DR衍生的自身肽。MS中的自身反应性T细胞识别HLA-DR衍生的自身肽/DR 15复合物。DR 15复合物触发MS中潜在的自身反应性T细胞HLA-DR 15通过交叉反应性/限制性形成自身反应性T细胞库HLA-DR 15分子呈递的免疫肽组将多发性硬化症的最重要的遗传和环境风险因素HLA-DR 15单倍型和EB病毒联系起来，通过形成交叉反应性CD 4 + T细胞库。
The HLA-DR15 haplotype is the strongest genetic risk factor for multiple sclerosis (MS), but our understanding of how it contributes to MS is limited. Because autoreactive CD4+ T cells and B cells as antigen-presenting cells are involved in MS pathogenesis, we characterized the immunopeptidomes of the two HLA-DR15 allomorphs DR2a and DR2b of human primary B cells and monocytes, thymus, and MS brain tissue. Self-peptides from HLA-DR molecules, particularly from DR2a and DR2b themselves, are abundant on B cells and thymic antigen-presenting cells. Furthermore, we identified autoreactive CD4+ T cell clones that can cross-react with HLA-DR-derived self-peptides (HLA-DR-SPs), peptides from MS-associated foreign agents (Epstein-Barr virus and Akkermansia muciniphila), and autoantigens presented by DR2a and DR2b. Thus, both HLA-DR15 allomorphs jointly shape an autoreactive T cell repertoire by serving as antigen-presenting structures and epitope sources and by presenting the same foreign peptides and autoantigens to autoreactive CD4+ T cells in MS. HLA-DR15 present abundant HLA-DR-derived self-peptides on B cells Autoreactive T cells in MS recognize HLA-DR-derived self-peptides/DR15 complexes Foreign peptides/DR15 complexes trigger potential autoreactive T cells in MS HLA-DR15 shape an autoreactive T cell repertoire by cross-reactivity/restriction The immunopeptidome presented by HLA-DR15 molecules links the most important genetic and environmental risk factors for multiple sclerosis, the HLA-DR15 haplotype and Epstein-Barr virus, by shaping a cross-reactive CD4+ T cell repertoire.
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