10779/crick.11637927.v1
Carrie R Willcox
Carrie R
Willcox
Pierre Vantourout
Pierre
Vantourout
Mahboob Salim
Mahboob
Salim
Iva Zlatareva
Iva
Zlatareva
Daisy Melandri
Daisy
Melandri
Leonor Zanardo
Leonor
Zanardo
Roger George
Roger
George
Svend Kjaer
Svend
Kjaer
Mark Jeeves
Mark
Jeeves
Fiyaz Mohammed
Fiyaz
Mohammed
Adrian C Hayday
Adrian C
Hayday
Benjamin E Willcox
Benjamin E
Willcox
Butyrophilin-like 3 directly binds a human Vγ4+ T cell receptor using a modality distinct from clonally-restricted antigen
The Francis Crick Institute
2020
T cell receptor
butyrophilin
complementarity determining region
gamma delta T cell
ligand
selection
Hayday FC001093
SB
1107 Immunology
Immunology
2020-01-17 16:56:39
Journal contribution
https://crick.figshare.com/articles/journal_contribution/Butyrophilin-like_3_directly_binds_a_human_V_4_T_cell_receptor_using_a_modality_distinct_from_clonally-restricted_antigen/11637927
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.