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

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Abstract
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‐κB 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 γ‐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.