Nonpeptide antigens, presentation mechanisms, and immunological memory of human Vγ2Vδ2 T cells: discriminating friend from foe through the recognition of prenyl pyrophosphate antigens

Abstract

Summary: Human Vγ2Vδ2 T cells play important roles in mediating immunity against microbial pathogens and have potent anti‐tumor activity. Vγ2Vδ2 T cells recognize the pyrophosphorylated isoprenoid intermediates (E)‐4‐hydroxy‐3‐methyl‐but‐2‐enyl pyrophosphate (HMBPP), an intermediate in the foreign 2‐C‐methyl‐d‐erythritol 4‐phosphate (MEP) pathway, and isopentenyl pyrophosphate (IPP), an intermediate in the self‐mevalonate pathway. Infection with bacteria and protozoa using the MEP pathway leads to the rapid expansion of Vγ2Vδ2 T cells to very high numbers through preferential recognition of HMBPP. Activated Vγ2Vδ2 T cells produce proinflammatory cytokines and chemokines, kill infected cells, secrete growth factors for epithelial cells, and present antigens to αβ T cells. Vγ2Vδ2 T cells can also recognize high levels of IPP in certain tumors and in cells treated with pharmacological agents, such as bisphosphonates and alkylamines, that block farnesyl pyrophosphate synthase. Activated Vγ2Vδ2 T cells are able to kill most tumor cells because of recognition by T‐cell receptor and natural killer receptors. The ubiquitous nature of the antigens converts essentially all Vγ2Vδ2 T cells to memory cells at an early age. Thus, primary infections with HMBPP‐producing bacteria are perceived by Vγ2Vδ2 T cells as a repeat infection. Extensive efforts are underway to harness these cells to treat a variety of cancers and to provide microbial immunity.