Abstract

SummaryButyrophilin (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.

Highlights

  • Few direct ligands of the gd T cell receptor (TCR) underpinning innate-like or adaptive responses are known

  • We show that a human Vg4 TCR binds the BTNL3 IgV domain via germline-encoded regions, somewhat analogous to superantigen binding to an ab TCR

  • The BTNL3 IgV Domain Directly and Binds Vg4 TCRs Previously, we demonstrated that exposure of Jurkat cells transduced with Vg4+ gd TCRs to 293T cells expressing BTNL3.8 heterodimers (293T.L3L8) led to CD69 upregulation and TCR downregulation, consistent with TCR triggering (Melandri et al, 2018)

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Summary

Introduction

Few direct ligands of the gd TCRs underpinning innate-like or adaptive responses are known. Adaptive processes highlight powerful clonotypic focusing even within specific V region subsets (e.g., Vd1 T cells, Vd1negVd2neg T cells, and Vg9negVd2 T cells), strongly suggesting that somatically recombined CDR3 regions are involved (Davey et al, 2018a). A diverse range of ligands has been proposed for such populations, including those few supported by evidence of direct TCR-ligand interaction, many of which favor roles for CDR3 residues (Willcox and Willcox, 2019)

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