Abstract

Upon recognition of peptide-MHC complexes by T cell receptors (TCR), the cognate T cells expand and differentiate into effector T cells to generate protective immunity. Despite the fact that any immune response generates a diverse set of TCR clones against a particular epitope, only a few clones are highly expanded in any immune response. Previous studies observed that the highest frequency clones usually control viral infections better than subdominant clones, but the reasons for this dominance among T cell clones are still unclear. Here, we used publicly available TCR amino acid sequences to study which factors determine whether a response becomes immunodominance (ID) per donor; we classified the largest T cell clone as the epitope-specific dominant clone and all the other clones as subdominant responses (SD). We observed a distinctively hydrophobic CDR3 in ID responses against a dominant epitope from influenza A virus, compared to the SD responses. The common V-J combinations were shared between ID and SD responses, suggesting that the biased V-J recombination events are restricted by epitope specificity; thus, the immunodominance is not directly determined by a bias combination of V and J genetic segments. Our findings reveal a close similarity of global sequence properties between dominant and subdominant clones of epitope-specific responses but detectable distinctive amino acid enrichments in ID. Taken together, we believe this first comparative study of immunodominant and subdominant TCR sequences can guide further studies to resolve factors determining the immunodominance of antiviral as well as tumor-specific T cell responses.

中文翻译：

---

确定针对显性表位的免疫显性反应的揭示因素

摘要

通过T细胞受体（TCR）识别肽-MHC复合物后，同源T细胞扩增并分化为效应T细胞，从而产生保护性免疫。尽管任何免疫应答都会产生针对特定表位的多种TCR克隆，但在任何免疫应答中只有少数几个克隆高度扩增。先前的研究发现，频率最高的克隆通常比次要克隆更好地控制病毒感染，但是在T细胞克隆中占主导地位的原因仍不清楚。在这里，我们使用了公开提供的TCR氨基酸序列来研究哪些因素决定了每个供体的反应是否变为免疫优势（ID）。我们将最大的T细胞克隆分类为表位特异性显性克隆，将所有其他克隆分类为次显性反应（SD）。与SD应答相比，我们在针对甲型流感病毒优势表位的ID应答中观察到了独特的疏水性CDR3。常见的VJ组合在ID和SD反应之间共享，这表明有偏见的VJ重组事件受到表位特异性的限制。因此，免疫优势不是直接由V和J基因片段的偏向组合决定的。我们的发现揭示了抗原决定簇特异性应答的显性和显性克隆之间的全局序列特性非常相似，但ID中可检测到独特的氨基酸富集。综上所述，我们认为对免疫显性和亚显性TCR序列的第一个比较研究可以指导进一步的研究，以解决决定抗病毒以及肿瘤特异性T细胞反应的免疫显性的因素。