Recognition of nonpeptide antigens by human Vγ9Vδ2 T cells requires contact with cells of human origin

It is becoming apparent that gammadelta T cells form an important part of the adaptive immune response. However, the ligands recognized by gammadelta T cell receptors (TCRs) and the exact biological function of the cells that express this receptor remain unclear. Numerous studies have shown that the dominant human peripheral blood subset of gammadelta T cells, which express a Vgamma9Vdelta2 TCR, can activate in response to low molecular weight nonpeptidic molecules. Some of these components have been purified from bacteria or parasites. We examined the activation of polyclonal gammadelta T cell lines, clones with Vgamma9Vdelta2 and Vgamma9Vdelta1 TCRs, and gammadelta T cells directly ex vivo in response to multiple phosphate, alkylamine and aminobisphosphonate (nBP) antigens and purified protein derivative from Mycobacterium tuberculosis (PPD). Vgamma9Vdelta2 T cells were able to respond to multiple small organic molecules of highly variable structure whereas cells expressing a similar Vgamma9 chain paired with a Vdelta1 chain failed to recognize these antigens. Thus, the TCR delta chain appears to make an important contribution to the recognition of these antigens. The kinetics of responses to alkylphosphate and alkylamine antigens differ from those of responses to the nBP pamidronate. These different classes of antigen are believed to have differed mechanisms of action. Such differences explain why nBPs can be pulsed onto antigen presenting cells (APCs) and still retain their ability to activate gammadelta T cells while alkylphosphate and alkylamine antigens cannot. We also demonstrate that a substantial proportion of the cells that produce IFNgamma directly ex vivo in response to PPD are gammadelta T cells and that gammadelta T cell activation requires contact with cells of human origin.