Abstract
The mechanistic requirements of antigen recognition by T cells expressing a γδ TCR has revealed important differences with those of αβ 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, γδ cells are represented in a variety of populations. The major subset of human peripheral blood γδ cells express Vγ9Vδ2 TCR heterodimers and are all stimulated by phosphorylated metabolites (commonly called phosphoantigens). Phosphoantigens are molecules with a very small mass and only stimulate Vγ9Vδ2 cells in the presence of antigen-presenting cells, suggesting a strict requirement for dedicated antigen-presenting molecules. Recent studies have identified butyrophilin (BTN) 3A1 as the molecule necessary to stimulate Vγ9Vδ2 cells. BTN3A1 extracellular, transmembrane, and cytoplasmic domains have different functions, including cognate interaction with the Vγ9Vδ2 TCR, binding of the phosphoantigens, and interaction with cytoplasmic proteins. This review mainly discusses the known molecular mechanisms of BTN3A1-mediated antigen presentation to γδ cells and proposes a model of phosphoantigen presentation, which integrates past and recent studies.
Highlights
Two types of TCR can be expressed in a mutually exclusive manner by T cells made up of either αβ or γδ chains
Initial studies showed the existence of human and mouse γδ cells recognizing MHC–peptide complexes expressed on the surface of antigen-presenting cells (APC) [10, 30,31,32]
The same population of γδ cells recognizes some tumor cells. This recognition is ascribed to the abnormally elevated production of isopentenyl pyrophosphate (IPP) by tumor cells, as result of changes in the regulation of their mevalonate metabolic pathway [47]. All of these findings show that γδ cells may cross-react to phosphorylated metabolites accumulating inside tumor cells and to metabolites released by bacterial cells in the microenvironment
Summary
Two types of TCR can be expressed in a mutually exclusive manner by T cells made up of either αβ or γδ chains. SMALL MOLECULES STIMULATING γδ TCR CELLS Several studies have identified both human and mouse γδ T cells that were activated by small peptides, carbohydrates, and haptens.
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