Non-instructional roles for Notch signaling in T cell development

Mammalian immunity requires the presence of a broad and diverse repertoire of antigen receptors that can recognize the virtually infinite number of pathogenic epitopes encountered over a lifetime of a host, along with the ability to flexibly mount organized and pathogen-specific immune responses, as orchestrated by cytokines and CD4+ helper T (Th) cells. The Notch signaling pathway plays a critical role both in the generation of the T cell repertoire and in Th cell differentiation. However, while Notch is well understood to instruct early T lineage development at the expense of alternate lineages, it is unclear how Notch regulates the differentiation of a common naïve progenitor into one of the many Th cell subsets. To clarify the molecular mechanism used by Notch to influence Th cell differentiation, the dynamics of Notch target binding and gene regulation were analyzed at early time points after T cell activation. Rather than finding that Notch signaling acts via the canonical instructional paradigm, these studies find that Notch acts as an unbiased integrator of environmental differentiation cues, such that it simultaneously promotes the differentiation of multiple inflammatory Th cell populations. These findings are supported by in vivo gain-of-function studies in which Notch signaling is constitutively activated in peripheral T cells. Unlike previous work showing that hyper-activation of the Notch pathway in T lineage progenitors yields aggressive T cell acute lymphoblastic leukemia, these mice go on to develop a lethal autoinflammatory disorder, resulting from the Notch pathway promoting the differentiation of Th1, Th2, and Th17 cells. Additionally, these studies reveal that Notch signaling acts to destabilize regulatory T cell differentiation. Altogether, the work presented in this thesis evinces a novel non-instructional paradigm for Notch signaling, with broad implications for our understanding of Th cell differentiation, hematopoietic development, and cancer biology