Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially regulate activation of peripheral T helper cells.
The Notch pathway is involved in cell differentiation processes in various organs and at several developmental stages. The importance of Notch for early T lymphocyte development is well established. Recently, Notch has been implicated in directing naive T helper cell differentiation towards the Th1, Th2 or regulatory T cell lineages. However, the molecular events underlying these processes are poorly understood. We show that the Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially affect early T cell activation and proliferation following T cell receptor cross-linking. Delta-like1 and Jagged1 induce a dose-dependent inhibition of early activation markers CD69 and CD25, as well as inhibition of proliferation after anti-CD3 stimulation of purified CD4+ T cells. Similarly, the rapid activation of transcription factors NF-AT, AP-1 and NF-kappaB is suppressed. In contrast, triggering of Notch by Delta-like4 enhances T cell activation and proliferation. The observed effects are dependent on simultaneous cross-linking of TCR and Notch but independent of gamma-secretase-mediated cleavage of Notch. These data suggest direct interference between Notch and early TCR signal transduction events, independent of the classical Notch pathway via release of the Notch intracellular domain. A Notch-mediated alteration of TCR signaling strength may contribute to the recently described modulation of naïve T cell differentiation by Notch ligands.
Rutz
Sascha
S
Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany.
Mordmüller
Benjamin
B
Sakano
Seiji
S
Scheffold
Alexander
A
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001798:Blood Proteins / Q000502:physiology*; D002135:Calcium-Binding Proteins; D049109:Cell Proliferation; D006023:Glycoproteins / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D000072100:Jagged-1 Protein; D019169:Jurkat Cells; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D001798:Blood Proteins; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins