Pnosphoantigen presentation to TCR γδ cells, a conundrum getting less gray zones

The mechanistic requirements of antigen recognition by T cells expressing a gamma delta TCR has revealed important differences with those of alpha beta TCR cells and, despite impressive new data generated in the very recent years, they remain poorly understood. Based on the structure of the TCR chains and the tissue distribution, gamma delta cells are represented in a variety of populations. The major subset of human peripheral blood gamma delta cells express V gamma 9V gamma delta TCR heterodimers and are all stimulated by phosphorylated metabolites (commonly called phosphoantigens). Phosphoantigens are molecules with a very small mass and only stimulate V gamma 9V gamma delta cells in the presence of antigen-presenting cells, suggesting a strict requirement for dedicated antigen-presenting molecules. Recent studies have identified butyrophilin (BIN) 3A1 as the molecule necessary to stimulate V gamma 9V gamma delta cells. BTN3A1 extracellular, transmembrane, and cytoplasmic domains have different functions, including cognate interaction with the V gamma 9V gamma delta TCR, binding of the phosphoantigens, and interaction with cytoplasmic proteins. This review mainly discusses the known molecular mechanisms of BTN3A1-mediated antigen presentation to gamma delta cells and proposes a model of phosphoantigen presentation, which integrates past and recent studies. Keywords: antigen presentation, gamma delta TCR, butyrophilin 3A1, infection control, tumor surveillance