V gamma 2V delta 2 T Cell Receptor Recognition of Prenyl Pyrophosphates Is Dependent on All CDRs

gamma delta T cells differ from alpha beta T cells in the Ags they recognize and their functions in immunity. Although most alpha beta TCRs recognize peptides presented by MHC class I or II, human gamma delta T cells expressing V gamma 2V delta 2 TCRs recognize nonpeptide prenyl pyrophosphates. To define the molecular basis for this recognition, the effect of mutations in the TCR CDR was assessed. Mutations in all CDR loops altered recognition and cover a large footprint. Unlike murine gamma delta TCR recognition of the MHC class Ib T22 protein, there was no CDR3 delta motif required for recognition because only one residue is required. Instead, the length and sequence of CDR3 gamma was key. Although a prenyl pyrophosphate-binding site was defined by Lys109 in J gamma 1.2 and Arg51 in CDR2 delta, the area outlined by critical mutations is much larger. These results show that prenyl pyrophosphate recognition is primarily by germline-encoded regions of the gamma delta TCR, allowing a high proportion of V gamma 2V delta 2 TCRs to respond. This underscores its parallels to innate immune receptors. Our results also provide strong evidence for the existence of an Ag-presenting molecule for prenyl pyrophosphates. The Journal of Immunology, 2010, 184: 6209-6222.