αβ TCR-mediated recognition: relevance to tumor-antigen discovery and cancer immunotherapy.
αβ TCR-mediated recognition: relevance to tumor-antigen discovery and cancer immunotherapy.
复制标题
DOI：
10.1158/2326-6066.cir-15-0042
复制
发表时间：
2015-04
影响因子：
10.1
通讯作者：
Reinherz EL
中科院分区：
文献类型：
--
作者：
Reinherz EL
αβ T淋巴细胞感知由感染性病原体、致癌性转化或化学或物理损伤诱导的宿主细胞体成分的扰动。通过胸腺中的T谱系发育产生了数百万至数十亿的这些淋巴细胞，每个淋巴细胞都具有克隆限制性表面T细胞受体（TCR）。单个TCR具有识别哺乳动物宿主必须能够检测的无数抗原中的不同“外来”肽的能力。TCR明确区分与主要组织相容性复合体（MHC）分子结合的外源肽和自身肽。这是一个令人生畏的挑战，因为MHC连接的肽组由数千种不同的肽组成，其中相关的非自身靶抗原通常以低数量嵌入，在数量级更高频率的自身肽中。在这篇免疫学硕士论文中，我将回顾TCR结构和伴随的机械生物学（涉及非线性反应）如何影响灵敏度和特异性，以满足这一要求。使用量化表位拷贝数的现有技术质谱物理检测方法评估人肿瘤细胞展示可以帮助告知提供保护和/或治疗性免疫的必要T细胞功能亲合力。未来合理的基于CD 8细胞毒性T细胞的疫苗可能会随之而来，靶向病毒诱导的癌症，其他非病毒免疫原性肿瘤，甚至潜在的非免疫原性肿瘤，其肽展示可以通过MHC结合药物故意改变以刺激免疫攻击。
αβ T lymphocytes sense perturbations in host cellular body components induced by infectious pathogens, oncogenic transformation or chemical or physical damage. Millions-billions of these lymphocytes are generated through T-lineage development in the thymus, each endowed with a clonally-restricted surface T-cell receptor (TCR). An individual TCR has the capacity to recognize a distinct “foreign” peptide among the myriad of antigens that the mammalian host must be capable of detecting. TCRs explicitly distinguish foreign from self peptides bound to major histocompatibility complex (MHC) molecules. This is a daunting challenge, given that the MHC-linked peptidome consists of thousands of distinct peptides with a relevant non-self target antigen often embedded at low number, among orders of magnitude higher frequency self-peptides. In this Masters of Immunology article, I shall review how TCR structure and attendant mechanobiology involving non-linear responses impact sensitivity as well as specificity to meet this requirement. Assessment of human tumor-cell display using state of the art mass spectrometry physical detection methods that quantify epitope copy number can help inform as to requisite T-cell functional avidity affording protection and/or therapeutic immunity. Future rational CD8 cytotoxic T cell-based vaccines may follow, targeting virally-induced cancers, other non-viral immunogenic tumors, and potentially even non-immunogenic tumors whose peptide display can be purposely altered by MHC-binding drugs to stimulate immune attack.