title: Notch signaling regulates antigen sensitivity of naive CD4+ T cells by tuning co-stimulation.
abstract: 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.
authors.affiliation: T Cell Development Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Laky
authors.affiliation: T Cell Development Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Sharron
authors.initials: S
authors.lastname: Evans
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Perez-Diez
authors.affiliation: T Cell Development Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. Electronic address: bfowlkes@nih.gov.
authors.forename: B J
authors.initials: BJ
authors.lastname: Fowlkes
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002277:Carcinoma / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D020239:Receptor Cross-Talk; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D047368:Tumor Burden / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D051880:Receptors, Notch; C064045:delta protein