Immunity | 黄志伟团队揭示BTNL3–BTNL8复合物激活γδ T细胞的分子机制

TL;DR - A cryo-EM study from Zhiwei Huang's team (Immunity, Aug 3, 2026) shows that intestinal epithelial BTNL3–BTNL8 forms a clamp-shaped tetramer that dimerizes Vγ4Vδ1 TCRs to trigger antigen-independent γδ T cell activation. Note: this is wet-lab structural immunology with no AI/computational-method component described.

• High-resolution cryo-EM reveals a 2:2:2 BTNL3–BTNL8–Vγ4Vδ1 TCR hexameric complex: extracellular IgC domains, transmembrane helices, and intracellular B30.2 domains build the heterodimer, and two heterodimers assemble via B30.2 into a clamp that grips two TCRs from both sides.
• No ligand density was seen in the B30.2 domains, indicating tetramerization is not induced by exogenous small-molecule antigen — unlike BTN2A1–BTN3A1, which requires phosphoantigen binding to BTN3A1's B30.2 domain.
• Selectivity for Vγ4 is mediated by the BTNL3 IgV domain via arginines at TCR positions 97 and 101; other Vγ subtypes (Vγ3, Vγ5, Vγ8, Vγ9) carry residues of differing size/charge there.
• Head-to-head TCR homodimerization (stabilized by CDR loop contacts) drives membrane clustering and enhanced downstream signaling; 2D classification of variants shows the mode is independent of CDR3 sequence or Vδ chain, and the dimer interface sterically overlaps CD1d/CD1a binding sites, excluding simultaneous lipid-antigen presentation.