BTN3A1‐antibodies and phosphoantigens: TCRVγ9Vδ2 “see” the difference

Human blood T lymphocytes express TCRV gamma 9V delta 2 and respond to nonpeptide phosphoantigens (PAgs) by a mysterious mechanism involving the BTN3A1 (CD277) molecule . BTN3A1 is a butyrophilin-like protein related to CD80, PD-L1, and MHC, and is either a presenting or a co-stimulatory molecule for PAgs. Although the precise roles and molecular interactions with the TCRV gamma 9V delta 2 are currently not determined, it is commonly thought that all TCRV gamma 9V delta 2 lymphocytes see' PAg and BTN3A1 together, presumably in a single molecular recognition event. But whether this recognition event could be reproduced in a simplified model was not addressed in previous studies. In this issue, Starick etal. (Eur. J. Immunol. 2017. 47: 982-992) compared the response of three TCRV gamma 9V delta 2 pairs of murine and human cell transfectants to PAg and anti-BTN3A1 antibodies using IL-2 release as a readout. The authors found that although the two murine transfectants responded similarly to either stimuli, one murine TCRV gamma 9V delta 2 transfectant reacted to PAgs but not to anti-BTN3A1 (mAb 20.1). Human transductants behave in a similar fashion, demonstrating that TCRV gamma 9V delta 2 lymphocytes differentiate PAg and BTN3A1 signals, while species of the transductants unmask this differential sensitivity. Indeed, understanding the puzzling mode of antigen recognition by T lymphocytes will be essential for developing T-cell-based immunotherapies, and the authors of this study now demonstrate that TCRV gamma 9V delta 2 lymphocytes are able to differentiate the PAg and BTN3A1 stimuli.