Structural Features of Nonpeptide Prenyl Pyrophosphates That Determine Their Antigenicity for Human γδ T Cells

Abstract

Human Vγ2Vδ2+ T cells proliferate in vivo during many microbial infections. We have found that Vγ2Vδ2+ T cells recognize nonpeptide prenyl pyrophosphates and alkylamines. We now have defined structural features that determine the antigenicity of prenyl pyrophosphates by testing synthetic analogs for bioactivity. We find that the carbon chain closest to the pyrophosphate moiety plays the major role in determining bioactivity. Changes in this area, such as the loss of a double bond, abrogated bioactivity. The loss of a phosphate from the pyrophosphate moiety also decreased antigenicity 100- to 200-fold. However, nucleotide monophosphates could be added with minimal changes in bioactivity. Longer prenyl pyrophosphates also retained bioactivity. Despite differences in CDR3 sequence, Vγ2Vδ2+ clones and a transfectant responded similarly. Ag docking into a Vγ2Vδ2 TCR model reveals a potential binding site in germline regions of the Vγ2Jγ1.2 CDR3 and Vδ2 CDR2 loops. Thus, Vγ2Vδ2+ T cells recognize a core carbon chain and pyrophosphate moiety. This recognition is relatively unaffected by additions at distal positions to the core Ag unit.