德国维尔茨堡大学Thomas Herrmann和英国伯明翰大学Benjamin E. Willcox合作在研究中取得进展。他们发现Butyrophilin-2A1（BTN2A1）直接结合Vγ9Vδ2TCR的种系编码区域，对于焦磷酸盐化合物（磷酸抗原或P-Ag）感测是必不可少的。相关论文于2020年3月9日发表在《免疫学》杂志上。

他们进行了辐射杂交筛选，以发现可增强Butyrophilin-3A1（BTN3A1）的P-Ag感应功能的直接TCR配体和辅助因子。这些实验确定了BTN2A1是识别Vγ9Vδ2T细胞所必需的。BTN2A1与BTN3A1协同作用，使接触P-Ag的细胞对Vγ9Vδ2TCR介导的反应敏感。表面等离振子共振实验建立了Vγ9Vδ2TCR，这是利用种系编码的Vγ9区直接结合BTN2A1 CFG-IgV结构域表面。值得注意的是，涉及P-Ag识别的体细胞重组CDR3环是不参与的。免疫沉淀显示紧密的细胞表面BTN2A1-BTN3A1关联独立于P-Ag刺激。因此，BTN2A1是对Vγ9Vδ2TCR识别至关重要的与BTN3A1连接的辅因子。此外，这些结果表明，P-Ag感测的复合配体模型，其中Vγ9Vδ2TCR与BTN2A1和以CDR3依赖性识别的其他配体直接相互作用。

据悉，Vγ9Vδ2T细胞以TCR依赖的方式对微生物和宿主来源的P-Ag作出反应。BTN3A1是一种与共刺激分子的B7家族结构相关的蛋白质，它是必需的，但不足以实现此过程。

附：英文原文

Title: Butyrophilin-2A1 Directly Binds Germline-Encoded Regions of the Vγ9Vδ2 TCR and Is Essential for Phosphoantigen Sensing

Author: Mohindar M. Karunakaran, Carrie R. Willcox, Mahboob Salim, Daniel Paletta, Alina S. Fichtner, Angela Noll, Lisa Starick, Anna Nhren, Charlotte R. Begley, Katie A. Berwick, Raphal A.G. Chaleil, Vincent Pitard, Julie Déchanet-Merville, Paul A. Bates, Brigitte Kimmel, Timothy J. Knowles, Volker Kunzmann, Lutz Walter, Mark Jeeves, Fiyaz Mohammed, Benjamin E. Willcox, Thomas Herrmann

Issue&Volume: 2020-03-09

Abstract: Vγ9Vδ2 T cells respond in a TCR-dependent fashion to both microbial and host-derived pyrophosphate compounds (phosphoantigens, or P-Ag). Butyrophilin-3A1 (BTN3A1), a protein structurally related to the B7 family of costimulatory molecules, is necessary but insufficient for this process. We performed radiation hybrid screens to uncover direct TCR ligands and cofactors that potentiate BTN3A1’s P-Ag sensing function. These experiments identified butyrophilin-2A1 (BTN2A1) as essential to Vγ9Vδ2 T cell recognition. BTN2A1 synergised with BTN3A1 in sensitizing P-Ag-exposed cells for Vγ9Vδ2 TCR-mediated responses. Surface plasmon resonance experiments established Vγ9Vδ2 TCRs used germline-encoded Vγ9 regions to directly bind the BTN2A1 CFG-IgV domain surface. Notably, somatically recombined CDR3 loops implicated in P-Ag recognition were uninvolved. Immunoprecipitations demonstrated close cell-surface BTN2A1-BTN3A1 association independent of P-Ag stimulation. Thus, BTN2A1 is a BTN3A1-linked co-factor critical to Vγ9Vδ2 TCR recognition. Furthermore, these results suggest a composite-ligand model of P-Ag sensing wherein the Vγ9Vδ2 TCR directly interacts with both BTN2A1 and an additional ligand recognized in a CDR3-dependent manner.

DOI: 10.1016/j.immuni.2020.02.014

Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30085-6