Genetic dissection of Id3-mediated pathways in gamma/delta lineage development

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γδ T cells represent a unique group of lymphocytes arising from the same thymic progenitors that also produce αβ T cells. Although these two groups of T cells are closely linked in development, they clearly play distinct roles in the immune system. In contrast to αβ T cells, which require help from innate immune cells, many γδ T cells appear to function as the first line of defense and can provide immediate responses to pathogens by secreting cytokines and chemokines. In this regard, γδ T cells perform important innate immune functions to help control infections and to facilitate the induction of adaptive immune responses. Thus far we know little, about the regulatory mechanisms that control the developmental timing and effector fates of individual functional groups of γδ T cells. Id3, a small nuclear protein, has been shown to play differential roles in lineage differentiation among different groups of γδ T cells. Id3 exerts its regulatory role by inhibiting the E-protein family of transcription factors, notably E2A and HEB, which directly regulate many lineage differentiation (c)vents including rearrangement and expression of the TCR γ and 5 genes. Although the importance of Id3 in regulating E-protein function during γδ lineage specification has been clearly established, the dynamic changes of downstream transcriptional networks are still poorly defined. We propose to use genetic means to distinguish the functions of Id3 at different stages and in different lineages of T cell development. In particular, the assessment of Id3-mediated pathways will be facilitated by genetic analysis involving the combination of conditional Id3, Id2, E2A, and HEB alleles. We will use this newly established genetic system to determine the mechanisms by which ld3 controls lineage choice between αβ and γδ T cell fate and lineage choice between different subtypes of γδ T cells. This genetic approach will be conducted in conjunction with the other three related projects included in this program project grant Together, we seek a comprehensive understanding of molecular pathways underlying γδ lineage choice and specification of effector function.