Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially regulate activation of peripheral T helper cells

作者：Rutz S; Mordmuller B; Sakano S; Scheffold A^*

来源：European Journal of Immunology, 2005, 35(8): 2443-2451.

DOI：10.1002/eji.200526294

• costimulation
• TCR signaling
• Notch
• T cell differentiation

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 Jaggedl differentially affect early T cell activation and proliferation following T cell receptor cross-linking. Delta-like1 and Jaggedl 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 kappa B 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 naive T cell differentiation by Notch ligands.

• 出版日期2005-8