Butyrophilin-2A1 Directly Binds Germline-Encoded Regions of the V?9V?2 TCR and Is Essential for Phosphoantigen Sensing.

ABSTRACT: V?9V?2 T cells respond in a TCR-dependent fashion to both microbial and host-derived pyrophosphate compounds (phosphoantigens, or P-Ag). Butyrophilin-3A1 (BTN3A1), a protein structurally related to the B7 family of costimulatory molecules, is necessary but insufficient for this process. We performed radiation hybrid screens to uncover direct TCR ligands and cofactors that potentiate BTN3A1's P-Ag sensing function. These experiments identified butyrophilin-2A1 (BTN2A1) as essential to V?9V?2 T cell recognition. BTN2A1 synergised with BTN3A1 in sensitizing P-Ag-exposed cells for V?9V?2 TCR-mediated responses. Surface plasmon resonance experiments established V?9V?2 TCRs used germline-encoded V?9 regions to directly bind the BTN2A1 CFG-IgV domain surface. Notably, somatically recombined CDR3 loops implicated in P-Ag recognition were uninvolved. Immunoprecipitations demonstrated close cell-surface BTN2A1-BTN3A1 association independent of P-Ag stimulation. Thus, BTN2A1 is a BTN3A1-linked co-factor critical to V?9V?2 TCR recognition. Furthermore, these results suggest a composite-ligand model of P-Ag sensing wherein the V?9V?2 TCR directly interacts with both BTN2A1 and an additional ligand recognized in a CDR3-dependent manner.

SUBMITTER: Karunakaran MM 

PROVIDER: S-EPMC7083227 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature