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

Human blood γδ T lymphocytes express TCRVγ9Vδ2 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 TCRVγ9Vδ2 are currently not determined, it is commonly thought that all TCRVγ9Vδ2 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 et al. (Eur. J. Immunol. 2017. 47: 982–992) compared the response of three TCRVγ9Vδ2 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 TCRVγ9Vδ2 transfectant reacted to PAgs but not to anti-BTN3A1 (mAb 20.1). Human transductants behave in a similar fashion, demonstrating that TCRVγ9Vδ2 lymphocytes differentiate PAg and BTN3A1 signals, while species of the transductants unmask this differential sensitivity. Indeed, understanding the puzzling mode of antigen recognition by γδ T lymphocytes will be essential for developing γδ T-cell-based immunotherapies, and the authors of this study now demonstrate that TCRVγ9Vδ2 lymphocytes are able to differentiate the PAg and BTN3A1 stimuli.

How the TCRVγ9Vδ2 expressed by most human blood γδ T lymphocytes confer specificity for phosphoantigens (PAg) and BTN3A1+ target cells was unclear. Here, Franchini et al. comment novel insights from the report by Starick et al., who carefully dissected these responses using human and murine transfectants for various TCRVγ9Vδ2.

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