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Updated: Aug 5, 2026

Simultaneous Quantification of Anti-vector and Anti-transgene-Specific CD8+ T Cells Via MHC I Tetramer Staining After Vaccination with a Viral Vector
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Butyrophilin-like 3 and 8 tetramers clamp Vγ4Vδ1 T cell receptors for antigen-independent activation

De Dong1, Huiling Li2, Yuwei Zhu2

  • 1HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China; Westlake Center for Genome Editing, Westlake Laboratory of Life Sciences and Biomedicine, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang, China.

Immunity
|August 3, 2026
PubMed

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.

Keywords:
BTNL3BTNL8TCR dimerizationantigen-independentcryo-EMγδ TCR

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