Up-regulation of gene related to anergy in lymphocytes is associated with Notch-mediated human T cell suppression.
A growing body of literature indicates that the Notch pathway can influence the activation and differentiation of peripheral murine T cells, though comparatively little is known about the effects of Notch signaling in human T cells. In the present report we demonstrate that Jagged-1-induced Notch signaling (using immobilized Jagged-1 fusion protein) during stimulation of purified human CD4+ and CD8+ T cells potently inhibits T cell proliferation and effector function, including both Th1- and Th2-associated cytokines. Inhibition of T cell activation is not due to apoptosis or disruption of proximal TCR signaling, but is associated with up-regulation of GRAIL (gene related to anergy in lymphocytes) in CD4+ T cells, with modest effects on other E3 ubiquitin ligases such as c-Cbl and Itch. When evaluated for its effects on CD4+ T cell differentiation, Jagged-1-mediated signaling inhibits T cell cytokine secretion with no significant effect on proliferative responses. Collectively, these data demonstrate that Notch signaling in human T cells induced by Jagged-1 promotes a novel form of T cell hyporesponsiveness that differs from anergy, whereby primary T cell proliferation and cytokine secretion are potently inhibited, and effector function but not proliferative capacity are ameliorated upon secondary stimulation.
Kostianovsky
Alex M
AM
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Maier
Lisa M
LM
Baecher-Allan
Clare
C
Anderson
Ana C
AC
Anderson
David E
DE
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D017635:Clonal Anergy / Q000235:genetics*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D000072100:Jagged-1 Protein; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D051381:Rats; D051880:Receptors, Notch / Q000378:metabolism / Q000502:physiology*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis* / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics* / Q000276:immunology
D002135:Calcium-Binding Proteins; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606275:Jag1 protein, rat; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; C520250:RNF128 protein, human; D044767:Ubiquitin-Protein Ligases