The CD46-Jagged1 interaction is critical for human TH1 immunity

G Le Friec, D Sheppard, P Whiteman, CM Karsten… - Nature …, 2012 - nature.com
G Le Friec, D Sheppard, P Whiteman, CM Karsten, SAT Shamoun, A Laing, L Bugeon…
Nature immunology, 2012nature.com
CD46 is a complement regulator with important roles related to the immune response. CD46
functions as a pathogen receptor and is a potent costimulator for the induction of interferon-γ
(IFN-γ)-secreting effector T helper type 1 (TH1) cells and their subsequent switch into
interleukin 10 (IL-10)-producing regulatory T cells. Here we identified the Notch family
member Jagged1 as a physiological ligand for CD46. Furthermore, we found that CD46
regulated the expression of Notch receptors and ligands during T cell activation and that …
Abstract
CD46 is a complement regulator with important roles related to the immune response. CD46 functions as a pathogen receptor and is a potent costimulator for the induction of interferon-γ (IFN-γ)-secreting effector T helper type 1 (TH1) cells and their subsequent switch into interleukin 10 (IL-10)-producing regulatory T cells. Here we identified the Notch family member Jagged1 as a physiological ligand for CD46. Furthermore, we found that CD46 regulated the expression of Notch receptors and ligands during T cell activation and that disturbance of the CD46-Notch crosstalk impeded induction of IFN-γ and switching to IL-10. Notably, CD4+ T cells from CD46-deficient patients and patients with hypomorphic mutations in the gene encoding Jagged1 (Alagille syndrome) failed to mount appropriate TH1 responses in vitro and in vivo, which suggested that CD46-Jagged1 crosstalk is responsible for the recurrent infections in subpopulations of these patients.
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