title: The CD46-Jagged1 interaction is critical for human TH1 immunity.
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 (T(H)1) 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 T(H)1 responses in vitro and in vivo, which suggested that CD46-Jagged1 crosstalk is responsible for the recurrent infections in subpopulations of these patients.
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Le Friec
authors.forename: Devon
authors.initials: D
authors.lastname: Sheppard
authors.forename: Pat
authors.initials: P
authors.lastname: Whiteman
authors.forename: Christian M
authors.initials: CM
authors.lastname: Karsten
authors.forename: Salley Al-Tilib
authors.initials: SA
authors.lastname: Shamoun
authors.forename: Adam
authors.initials: A
authors.lastname: Laing
authors.forename: Laurence
authors.initials: L
authors.lastname: Bugeon
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Dallman
authors.forename: Teresa
authors.initials: T
authors.lastname: Melchionna
authors.forename: Chandramouli
authors.initials: C
authors.lastname: Chillakuri
authors.forename: Richard A
authors.initials: RA
authors.lastname: Smith
authors.forename: Christian
authors.initials: C
authors.lastname: Drouet
authors.forename: Lionel
authors.initials: L
authors.lastname: Couzi
authors.forename: Veronique
authors.initials: V
authors.lastname: Fremeaux-Bacchi
authors.forename: Jörg
authors.initials: J
authors.lastname: Köhl
authors.forename: Simon N
authors.initials: SN
authors.lastname: Waddington
authors.forename: James M
authors.initials: JM
authors.lastname: McDonnell
authors.forename: Alastair
authors.initials: A
authors.lastname: Baker
authors.forename: Penny A
authors.initials: PA
authors.lastname: Handford
authors.forename: Susan M
authors.initials: SM
authors.lastname: Lea
authors.forename: Claudia
authors.initials: C
authors.lastname: Kemper
mesh_terms: D000328:Adult; D016738:Alagille Syndrome / Q000235:genetics / Q000276:immunology; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D000072100:Jagged-1 Protein; D008213:Lymphocyte Activation; D051916:Membrane Cofactor Protein / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D034622:RNA Interference; D034741:RNA, Small Interfering; D000072099:Serrate-Jagged Proteins; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D051178:alpha Catenin / Q000235:genetics
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D051916:Membrane Cofactor Protein; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D000072099:Serrate-Jagged Proteins; D051178:alpha Catenin; D016753:Interleukin-10; D007371:Interferon-gamma