Notch signaling regulates antigen sensitivity of naive CD4+ T cells by tuning co-stimulation

Immunity. 2015 Jan 20;42(1):80-94. doi: 10.1016/j.immuni.2014.12.027. Epub 2015 Jan 1.


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology
  • Antigens, Neoplasm / metabolism
  • CD28 Antigens / metabolism
  • CD4-Positive T-Lymphocytes / immunology*
  • Carcinoma / immunology*
  • Cell Proliferation
  • Cells, Cultured
  • Cytokines / metabolism
  • Female
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lymphocyte Activation / genetics
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Neoplasm Transplantation
  • Peptide Fragments / immunology
  • Peptide Fragments / metabolism
  • Receptor Cross-Talk*
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Notch / genetics
  • Receptors, Notch / immunology
  • Receptors, Notch / metabolism*
  • Signal Transduction* / genetics
  • Tumor Burden / genetics


  • Antigens, Neoplasm
  • CD28 Antigens
  • Cytokines
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Peptide Fragments
  • Receptors, Antigen, T-Cell
  • Receptors, Notch
  • delta protein