Notch3 Inhibition in Myelin-Reactive T Cells Down-Regulates Protein Kinase Cθ and Attenuates Experimental Autoimmune Encephalomyelitis
- 15 February 2008
- journal article
- research article
- Published by The American Association of Immunologists
- Vol. 180 (4), 2634-2640
- https://doi.org/10.4049/jimmunol.180.4.2634
Abstract
Among its varied functions, Notch signaling is involved in peripheral T cells responses. The activation and polarization of CD4+ T cells toward a Th1 lineage are essential steps in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Inhibition of all four Notch receptors with a γ-secretase inhibitor was shown to block Th1-type polarization and to attenuate the symptoms of experimental autoimmune encephalomyelitis. In this study, we have examined the role of individual Notch receptors in proliferation, cytokine production, and encephalitogenic potential of PLP-reactive T cells. Specific induction of Notch1 and Notch3 transcripts were noted in PLP-reactive T cells upon Ag stimulation. However, using γ-secretase inhibitor and Abs blocking distinct Notch receptors, we have found that selective inhibition of Notch3, but not Notch1, receptor abrogated proliferation, Th1- and Th17-type responses of PLP-reactive T cells. Moreover, Notch3 inhibition in T cells correlated with the down-regulated expression of protein kinase Cθ, a kinase with important regulatory function within mature T cells. Thus, selective inhibition of the Notch3 receptor may have important effects on peripheral T cell responses and may offer a new attractive target in treating autoimmune diseases, including multiple sclerosis.Keywords
This publication has 35 references indexed in Scilit:
- Direct Regulation of Gata3 Expression Determines the T Helper Differentiation Potential of NotchImmunity, 2007
- Notch Directly Regulates Gata3 Expression during T Helper 2 Cell DifferentiationImmunity, 2007
- CD8− DCs induce IL-12–independent Th1 differentiation through Delta 4 Notch-like ligand in response to bacterial LPSThe Journal of Experimental Medicine, 2007
- Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially regulate activation of peripheral T helper cellsEuropean Journal of Immunology, 2005
- IMMUNOLOGY OF MULTIPLE SCLEROSISAnnual Review of Immunology, 2005
- Notch1 expression on T cells is not required for CD4+ T helper differentiationEuropean Journal of Immunology, 2004
- JNK is required for effector T-cell function but not for T-cell activationNature, 2000
- PKC-θ is required for TCR-induced NF-κB activation in mature but not immature T lymphocytesNature, 2000
- Notch Signaling: Cell Fate Control and Signal Integration in DevelopmentScience, 1999
- Co-stimulation-dependent activation of a JNK-kinase in T lymphocytesEuropean Journal of Immunology, 1998