近日，英国伯明翰大学Benjamin E. Willcox与伦敦国王学院Adrian C. Hayday等研究人员合作发现，嗜乳脂蛋白样3蛋白使用与克隆限制性抗原不同的模式直接结合人Vγ4阳性T细胞受体。这一研究成果发表在2019年11月19日出版的《免疫》上。

研究人员表示，嗜乳脂蛋白（BTN）和嗜乳脂蛋白样蛋白（BTNL / Btnl）异聚体是人和小鼠γδT细胞亚群的主要调节者，但围绕它们是否代表直接的γδT细胞受体（TCR）配体存在相当大的争议。

研究人员证明了BTNL3 IgV结构域直接且特异性地与人Vγ4+ TCR“ LES”结合，其亲和力（约15–25μM）可与许多αβTCR肽主要组织相容性复合物相互作用相媲美。生殖系编码的Vγ4CDR2和HV4环中的突变大大降低了对表达BTNL3-BTNL8的细胞的结合和T细胞反应，而体细胞重组的CDR3环中突变没有这一效果。

相反，CDR3γ和CDR3δ环介导LES TCR与内皮蛋白C受体（一种克隆受限的自身抗原）结合，而CDR1、CDR2或HV4的贡献最小。因此，γδTCR可以采用两种不同的结合方式：通过BTNL/BTN分子介导亚群特异性调节的非克隆型、超抗原样相互作用，以及介导适应性γδT细胞的CDR3依赖性抗体样相互作用。研究人员对这些发现如何广泛应用于γδT细胞调节也进行了测试。

附：英文原文

Title: Butyrophilin-like 3 Directly Binds a Human Vγ4+ T Cell Receptor Using a Modality Distinct from Clonally-Restricted Antigen

Author: Carrie R. Willcox, Pierre Vantourout, Mahboob Salim, Iva Zlatareva, Daisy Melandri, Leonor Zanardo, Roger George, Svend Kjaer, Mark Jeeves, Fiyaz Mohammed, Adrian C. Hayday, Benjamin E. Willcox

Issue&Volume: 2019/11/19

Abstract: Butyrophilin (BTN) and butyrophilin-like (BTNL/Btnl) heteromers are major regulators of human and mouse γδ T cell subsets, but considerable contention surrounds whether they represent direct γδ T cell receptor (TCR) ligands. We demonstrate that the BTNL3 IgV domain binds directly and specifically to a human Vγ4+ TCR, “LES” with an affinity (～15–25 μM) comparable to many αβ TCR-peptide major histocompatibility complex interactions. Mutations in germline-encoded Vγ4 CDR2 and HV4 loops, but not in somatically recombined CDR3 loops, drastically diminished binding and T cell responsiveness to BTNL3-BTNL8-expressing cells. Conversely, CDR3γ and CDR3δ loops mediated LES TCR binding to endothelial protein C receptor, a clonally restricted autoantigen, with minimal CDR1, CDR2, or HV4 contributions. Thus, the γδ TCR can employ two discrete binding modalities: a non-clonotypic, superantigen-like interaction mediating subset-specific regulation by BTNL/BTN molecules and CDR3-dependent, antibody-like interactions mediating adaptive γδ T cell biology. How these findings might broadly apply to γδ T cell regulation is also examined.

DOI: 10.1016/j.immuni.2019.09.006

Source: https://www.cell.com/immunity/fulltext/S1074-7613(19)30402-9