Opportunities and challenges in development of phosphoantigens as Vγ9Vδ2 T cell agonists

In contrast to T cells that express the more prevalent 0, p T cell receptor and respond to peptide antigens, T cells that express the V gamma 9V delta 2 T cell receptor detect and respond to non-peptide phosphorous-containing small molecules known as phosphoantigens. Because gamma delta T cells are early responders to infections and malignancies, it has been suggested that stimulation of their activity with small molecule phosphoantigen drugs may hold promise for therapeutic interventions. Recent studies have greatly advanced our knowledge of phosphoantigens as well as their cellular receptors. At the same time, clinical trials of phosphoantigens have suggested that development of these V gamma 9V delta 2 T cell agonists has met unexpected challenges. In this commentary, we summarize the biology that underlies phosphoantigen activity and discuss the structural features of synthetic phosphoantigens that affect both their ability to stimulate V gamma 9V delta 2 T cells and their potential as therapeutic agents. (C) 2014 Elsevier Inc. All rights reserved.