Immunity & infection

Oral

Sensing of Isoprenoid Metabolites by Human vγ2vδ2 T Cells Is Critically Dependent on the Intracellular Coiled Coil Domain of Butyrophilin 3a1

Wednesday, June 14
6:15 PM - 7:45 PM

Vγ2Vδ2 T cells play important roles in human immunity to pathogens and in cancer immunotherapy by responding to isoprenoid metabolites such as (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) and isopentenyl pyrophosphate. The immunoglobulin superfamily protein, butyrophilin 3A1 (BTN3A1), is required for this stimulation. HMBPP is not an antigen but instead is sensed by binding to the B30.2 domain of BTN3A1. How this binding is detected by Vγ2Vδ2 TCRs is unclear. BTN3A1 is a homodimer with extracellular IgV/IgC domains (ECD) linked to intracellular B30.2 domains by an intracellular coiled coil domain. HMBPP binding could alter the conformation of the BTN3 ECD through "inside-out" signaling allowing Vγ2Vδ2 TCR recognition. This could involve only BTN3A1 or all three BTN3 isoforms. We find that mutagenesis of 39 BTN3A1 ECD residues had no effect whereas mutagenesis of coiled coil residues either abrogated (mid-region) or decreased (proximal and distal regions) HMBPP stimulation. Thus, Vγ2Vδ2 TCRs do not appear to recognize BTN3A1 ECDs with intramolecular conformational changes. However, recognition of conformational changes in BTN3A2 and BTN3A3 ECDs induced by intermolecular interactions is possible. Alternatively, Vγ2Vδ2 TCRs may bind to the ECD of a protein recruited to the intracellular tail of BTN3A1 upon B30.2 binding to HMBPP. In all mechanisms, the coiled coil domain of BTN3A1 plays a critical role. Coiled coil regions are predicted for most butyrophilins with B30.2 domains and they likely function as essential rod-like helical scaffolds to allow sensing by B30.2 domains.

Craig T. Morita

Professor
University of Iowa / Veterans Health Care System

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    Hong Wang

    Research Scientist
    University of Iowa / Veterans Health Care System

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      Send Email for Hong Wang


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