γδTCR ligands and lineage commitment

Two major T lymphocyte lineages – αβ and γδ T cells – develop in the thymus from common precursors. Differentiation of both lineages requires signals coming from TCRs. Development of αβ T cells is driven at early stages by signaling from the pre-TCR, most likely in a ligand-independent fashion, and later – by signals delivered by αβTCRs binding to their ligands – classical or non-classical MHC molecules. γδ lineage cells likewise require TCR signaling for their differentiation. Recent work from several groups suggests that TCR signaling not only ensures the developmental progression towards αβ and γδ lineages but that signal strength instructs lineage fate: weaker TCR signal results in αβ and stronger—in γδ lineage commitment. However, as most γδTCRs remain orphan receptors, it is still debated whether strong signals from γδTCRs in development are generated in a ligand-dependent manner (as in the case of αβTCRs), ligand-independent manner (as for pre-TCR) or both. Here we summarize evidence supporting a possible role for ligands in γδ T cell lineage commitment and the generation of γδ sublineages.