HLA class I-associated expansion of TRBV11-2 T cells in multisystem inflammatory syndrome in children
HLA class I-associated expansion of TRBV11-2 T cells in multisystem inflammatory syndrome in children
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DOI：
10.1172/jci146614
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发表时间：
2021-05-17
影响因子：
15.9
通讯作者：
Arditi, Moshe
中科院分区：
文献类型：
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作者：
Porritt, Rebecca A.;Paschold, Lisa;Arditi, Moshe
儿童多系统炎性综合征（MIS-C）是一种与SARS-CoV-2感染相关的高炎症综合征，与细菌超抗原引发的中毒性休克综合征具有相同的临床特征。对不同V β链的超抗原特异性导致V β偏斜，由此具有特异性V β链和不同抗原特异性的T细胞在T细胞受体（TCR）库中过度表达。在这里，我们描述了MIS-C患者的TCR库，发现TCR β可变基因11-2（TRBV 11 -2）的显著扩增，TRBV 112 T细胞占据了高达24%的克隆T细胞空间，这与MIS-C的严重程度和血清细胞因子水平相关。对MIS-C扩增的TRBV 11 -2克隆的TRBJ基因使用和互补决定区3（CDR 3）长度分布的分析显示了广泛的连接多样性。TRBV 11 -2扩增的患者共享HLA I类等位基因A02、B35和C 04，表明我们认为这是一种非CDR 3依赖性T细胞扩增的新机制。计算机模拟表明，TRBV 11 -2编码的V β链（V β 21.3）中的多酸残基与SARS-CoV-2刺突糖蛋白的超抗原样基序强烈相互作用，表明未加工的SARS-CoV-2刺突可能直接介导TRBV 11 -2扩增。总体而言，我们的数据表明，SARS-CoV-2刺突和TCR之间的CDR 3非依赖性相互作用导致T细胞扩增和可能的活化，这可能是MIS-C临床表现的原因。
Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory syndrome associated with SARS-CoV-2 infection, shares clinical features with toxic shock syndrome, which is triggered by bacterial superantigens. Superantigen specificity for different V beta chains results in V beta skewing, whereby T cells with specific V beta chains and diverse antigen specificity are overrepresented in the T cell receptor (TCR) repertoire. Here, we characterized the TCR repertoire of MIS-C patients and found a profound expansion of TCR beta variable gene 11-2 (TRBV11-2), with up to 24% of clonal T cell space occupied by TRBV112 T cells, which correlated with MIS-C severity and serum cytokine levels. Analysis of TRBJ gene usage and complementaritydetermining region 3 (CDR3) length distribution of MIS-C expanded TRBV11-2 clones revealed extensive junctional diversity. Patients with TRBV11-2 expansion shared HLA class I alleles A02, B35, and C04, indicating what we believe is a novel mechanism for CDR3-independent T cell expansion. In silico modeling indicated that polyacidic residues in the V beta chain encoded by TRBV11-2 (V beta 21.3) strongly interact with the superantigen-like motif of SARS-CoV-2 spike glycoprotein, suggesting that unprocessed SARS-CoV-2 spike may directly mediate TRBV11-2 expansion. Overall, our data indicate that a CDR3-independent interaction between SARS-CoV-2 spike and TCR leads to T cell expansion and possibly activation, which may account for the clinical presentation of MIS-C.