Notch Signaling Regulates Antigen Sensitivity of Naive CD4+ T Cells by Tuning Co-stimulation

Adaptive immune responses begin when naive CD4+ T cells engage peptide+major histocompatibility complex class II and co-stimulatory molecules on antigen-presenting cells (APCs). Notch signaling can influence effector functions in differentiated CD4+ T helper and T regulatory cells. Whether and how ligand-induced Notch signaling influences the initial priming of CD4+ T cells has not been addressed. We have found that Delta Like Ligand 4 (DLL4)-induced Notch signaling potentiates phosphatidylinositol 3-OH kinase (PI3K)-dependent signaling downstream of the T cell receptor+CD28, allowing naive CD4+ T cells to respond to lower doses of antigen. In vitro, DLL4-deficient APCs were less efficient stimulators of CD4+ T cell activation, metabolism, proliferation, and cytokine secretion. With deletion of DLL4 from CD11c+ APCs in vivo, these deficits translated to an impaired ability to mount an effective CD4+-dependent anti-tumor response. These data implicate Notch signaling as an important regulator of adaptive immune responses. •Notch enhances the magnitude, kinetics, and quality of primary immune responses•Ligand-induced Notch signaling increases the Ag sensitivity of naive CD4+ T cells•In CD4+ T cells, Notch signaling potentiates PI3K signaling downstream of TCR+CD28•DLL4 on APCs is physiologically important for CD4+-mediated T cell responses in vivo Notch signaling influences effector functions in fully differentiated CD4+ T cells. Laky et al. show that Notch can also enhance T cell activation during the priming phase by increasing the frequency of CD4+ T cells that respond and by improving the quality of the response on a per-cell basis.