Id3 is a critical mediator of lineage commitment and functional maturation of γδ-T cells (36.63)

Abstract

Abstract αβ and γδ T cells are thought to arise from a common precursor during development in the thymus. However, the basis for separation of these lineages is poorly understood. Previously, we showed that strong TCR signals promote γδ lineage choice, while weaker signals favor adoption of the αβ lineage. Here we show that the HLH factor Id3 plays a defining role in this process. We found that Id3 is required for strong TCR signals to both promote adoption of the γδ-fate and oppose the αβ-fate outcome. Importantly, the effects of Id3-deficiency on γδ lineage cells appear to differ depending on the γδ subset. In Id3-/- mice, development of the Vγ2 subset and Vγ3 dendritic epidermal T cell (DETC) subset are both reduced, while innate type NK γδ T cells bearing a Vγ1.1/Vδ6.3 TCR are dramatically expanded. Our analysis suggests that the γδ subsets whose development is impaired by Id3-deficiency are dependent on TCR signals of intermediate intensity. In contrast, those which are expanded (Vγ1.1Vδ6.3) in Id3-deficient mice may normally be deleted, perhaps by high-affinity ligand. In support this view, KN6 γδ TCR transgenic thymocytes normally deleted by high affinity ligand (T-10/22b) are rescued by Id3-defciency. Likewise, the junctional sequences of the TCR subunits of Vγ1.1Vδ6.3 T cells in Id3-/- exhibited almost no variation, suggesting strong selective pressure. These results indicate that Id3 not only in regulates fate selection, but also in shapes the γδ TCR repertoire.