美国布莱根妇女医院Stephen J. Elledge团队近期取得重要工作进展，他们研究利用合成细胞电路高通量发现MHC I类和II类限制性T细胞表位。相关研究成果2024年7月2日在线发表于《自然—生物技术》杂志上。

据介绍，抗原发现技术主要集中在主要组织相容性复合体（MHC）I类限制性人类T细胞受体（TCR）上，而MHC II类限制性和小鼠TCR反应的方法相对研究较少。

研究人员开发了抗原肽的TCR定位（TCR-MAP），这是一种抗原发现方法，使用永生T细胞中合成的TCR刺激电路来激活分选酶介导的MHC上表达加工肽的工程抗原呈递细胞（APC）的标记。活的、标记的APC可以通过测序直接纯化以进行去卷积，从而使具有未知特异性的TCR能够在合并的筛选环境中对照条形码肽库进行查询。TCR-MAP以高通量和高灵敏度准确捕捉MHC I类限制性和II类限制性TCR的自身反应性或病毒反应性。研究人员阐明了靶向癌症/睾丸黑色素瘤相关抗原A3的临床TCR的有问题的交叉反应性，并发现了小鼠中引起心肌梗死的自身反应T细胞的靶点。

总之，TCR-MAP有可能在癌症、传染病和自身免疫的背景下加速T细胞抗原的发现工作。

附：英文原文

Title: High-throughput discovery of MHC class I- and II-restricted T cell epitopes using synthetic cellular circuits

Author: Kohlgruber, Ayano C., Dezfulian, Mohammad H., Sie, Brandon M., Wang, Charlotte I., Kula, Tomasz, Laserson, Uri, Larman, H. Benjamin, Elledge, Stephen J.

Issue&Volume: 2024-07-02

Abstract: Antigen discovery technologies have largely focused on major histocompatibility complex (MHC) class I-restricted human T cell receptors (TCRs), leaving methods for MHC class II-restricted and mouse TCR reactivities relatively undeveloped. Here we present TCR mapping of antigenic peptides (TCR-MAP), an antigen discovery method that uses a synthetic TCR-stimulated circuit in immortalized T cells to activate sortase-mediated tagging of engineered antigen-presenting cells (APCs) expressing processed peptides on MHCs. Live, tagged APCs can be directly purified for deconvolution by sequencing, enabling TCRs with unknown specificity to be queried against barcoded peptide libraries in a pooled screening context. TCR-MAP accurately captures self-reactivities or viral reactivities with high throughput and sensitivity for both MHC class I-restricted and class II-restricted TCRs. We elucidate problematic cross-reactivities of clinical TCRs targeting the cancer/testis melanoma-associated antigen A3 and discover targets of myocarditis-inciting autoreactive T cells in mice. TCR-MAP has the potential to accelerate T cell antigen discovery efforts in the context of cancer, infectious disease and autoimmunity.

DOI: 10.1038/s41587-024-02248-6

Source: https://www.nature.com/articles/s41587-024-02248-6