澳大利亚墨尔本大学Adam P. Uldrich等研究人员合作发现，Vγ9Vδ2 T细胞识别嗜乳脂蛋白2A1和3A1异聚体。该项研究成果于2024年7月16日在线发表在《自然—免疫学》杂志上。

研究人员发现，γδ T细胞抗原受体（γδTCR）与BTN2A1复合物的晶体结构揭示了BTN2A1与γδTCR侧面结合，使顶端的TCR表面可用。研究人员发现第二个γδTCR配体通过与这个可接近的顶端表面结合，在BTN3A1依赖性方式下共同结合γδTCR。BTN2A1和BTN3A1也在顺式互相直接作用，结构分析揭示了W形异源多聚物的形成。

BTN2A1–BTN3A1相互作用涉及BTN2A1和BTN3A1分别用于介导γδTCR相互作用的相同表位；实际上，将BTN2A1和BTN3A1锁在一起会阻碍它们与γδTCR的相互作用，进而支持了一种模型，即这两个γδTCR配体结合位点依赖于对隐蔽BTN表位的可及性。这些发现揭示了一种新的免疫激活模式，其中γδTCR通过感知BTN复合物上的双表位来激发免疫反应。

据悉，嗜乳脂蛋白（BTN）分子作为T细胞免疫的关键调节因子正逐渐受到关注，但其如何触发细胞介导的反应仍然理解不透彻。

附：英文原文

Title: Vγ9Vδ2 T cells recognize butyrophilin 2A1 and 3A1 heteromers

Author: Fulford, Thomas S., Soliman, Caroline, Castle, Rebecca G., Rigau, Marc, Ruan, Zheng, Dolezal, Olan, Seneviratna, Rebecca, Brown, Hamish G., Hanssen, Eric, Hammet, Andrew, Li, Shihan, Redmond, Samuel J., Chung, Amy, Gorman, Michael A., Parker, Michael W., Patel, Onisha, Peat, Thomas S., Newman, Janet, Behren, Andreas, Gherardin, Nicholas A., Godfrey, Dale I., Uldrich, Adam P.

Issue&Volume: 2024-07-16

Abstract: Butyrophilin (BTN) molecules are emerging as key regulators of T cell immunity; however, how they trigger cell-mediated responses is poorly understood. Here, the crystal structure of a gamma-delta T cell antigen receptor (γδTCR) in complex with BTN2A1 revealed that BTN2A1 engages the side of the γδTCR, leaving the apical TCR surface bioavailable. We reveal that a second γδTCR ligand co-engages γδTCR via binding to this accessible apical surface in a BTN3A1-dependent manner. BTN2A1 and BTN3A1 also directly interact with each other in cis, and structural analysis revealed formation of W-shaped heteromeric multimers. This BTN2A1–BTN3A1 interaction involved the same epitopes that BTN2A1 and BTN3A1 each use to mediate the γδTCR interaction; indeed, locking BTN2A1 and BTN3A1 together abrogated their interaction with γδTCR, supporting a model wherein the two γδTCR ligand-binding sites depend on accessibility to cryptic BTN epitopes. Our findings reveal a new paradigm in immune activation, whereby γδTCRs sense dual epitopes on BTN complexes.

DOI: 10.1038/s41590-024-01892-z

Source: https://www.nature.com/articles/s41590-024-01892-z