Adaptive immune responses protect against infection with dengue virus (DENV), yet cross-reactivity with distinct serotypes can precipitate life-threatening clinical disease. We found that clonotypes expressing the T cell antigen receptor (TCR) β-chain variable region 11 (TRBV11-2) were 'preferentially' activated and mobilized within immunodominant human-leukocyte-antigen-(HLA)-A*11:01-restricted CD8⁺ T cell populations specific for variants of the nonstructural protein epitope NS3₁₃₃ that characterize the serotypes DENV1, DENV3 and DENV4. In contrast, the NS3₁₃₃-DENV2-specific repertoire was largely devoid of such TCRs. Structural analysis of a representative TRBV11-2⁺ TCR demonstrated that cross-serotype reactivity was governed by unique interplay between the variable antigenic determinant and germline-encoded residues in the second β-chain complementarity-determining region (CDR2β). Extensive mutagenesis studies of three distinct TRBV11-2⁺ TCRs further confirmed that antigen recognition was dependent on key contacts between the serotype-defined peptide and discrete residues in the CDR2β loop. Collectively, these data reveal an innate-like mode of epitope recognition with potential implications for the outcome of sequential exposure to heterologous DENVs.

中文翻译：

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种系偏差决定了常见登革热病毒特异性 CD8+ T 细胞反应中的跨血清型反应性。

适应性免疫反应可预防登革热病毒 (DENV) 感染，但与不同血清型的交叉反应可引发危及生命的临床疾病。我们发现表达 T 细胞抗原受体 (TCR) β-链可变区 11 (TRBV11-2) 的克隆型在免疫显性人类白细胞抗原-(HLA)-A*11:01-restricted 中“优先”激活和动员CD8 ⁺ T 细胞群对表征血清型 DENV1、DENV3 和 DENV4的非结构蛋白表位 NS3 _{133的变体具有特异性。}相比之下，NS3 ₁₃₃ -DENV2 特定的曲目在很大程度上没有此类 TCR。^{代表性 TRBV11-2 +}的结构分析TCR 表明，跨血清型反应性受第二个 β 链互补决定区 (CDR2β) 中可变抗原决定簇和种系编码残基之间的独特相互作用控制。对三种不同的 TRBV11-2 ⁺ TCR 的广泛诱变研究进一步证实，抗原识别依赖于血清型定义的肽和 CDR2β 环中离散残基之间的关键接触。总的来说，这些数据揭示了一种类似于先天的表位识别模式，对连续暴露于异源 DENV 的结果具有潜在影响。