22KK

Cryo-EM structure of the BTNL3-BTNL8-TCR complex

Summary for 22KK

• Entry DOI: 10.2210/pdb22kk/pdb
• EMDB information: 68398
• Descriptor: Butyrophilin-like protein 3, Butyrophilin-like protein 8, TCR, ... (4 entities in total)
• Functional Keywords: cryo-em, immune, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 356493.83

Authors

Dong, D.,Zhu, Y.,Huang, Z. (deposition date: 2026-01-14, release date: 2026-08-26)

Primary citation

Dong, D.,Li, H.,Zhu, Y.,Lu, Z.,Zhu, J.,Tian, X.,Huang, Z.
Butyrophilin-like 3 and 8 tetramers clamp V gamma 4V delta 1 T cell receptors for antigen-independent activation.
Immunity, 2026

PubMed Abstract: BTNL3 and BTNL8, butyrophilin-like (BTNL) family receptors, are predominantly expressed on intestinal epithelial cells. The BTNL3-BTNL8 complex selectively activates human Vγ4⁺ T cells, which play critical roles in intestinal immune homeostasis and tissue damage repair. Here, we report the structure of the BTNL3-BTNL8-Vγ4Vδ1 T cell receptor (TCR) complex. The structure reveals that BTNL3-BTNL8 forms an antigen-independent tetramer, in contrast to the phosphoantigen-driven association of BTN2A1-BTN3A1. Two BTNL3-BTNL8 heterodimers clamp a head-to-head TCR homodimer to form a 2:2:2 BTNL3:BTNL8:Vγ4Vδ1 TCR complex, with the Vγ4 HV4 and CDR2 loops jointly engaging BTNL3. Structural alignment indicates that the CD1d binding site on TCR overlaps spatially with one monomer within a TCR dimer, suggesting that TCR dimerization sterically precludes simultaneous engagement of CD1d molecules. Together, our results elucidate the structural mechanism of BTNL3-BTNL8-mediated engagement and activation of Vγ4Vδ1 TCR, offering insights into γδ TCR signaling initiation.

PubMed: 42546693
DOI: 10.1016/j.immuni.2026.07.004

Experimental method

ELECTRON MICROSCOPY (3.1 Å)