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The CD46-Jagged1 interaction is critical for human TH1 immunity

2012; Nature Portfolio; Volume: 13; Issue: 12 Linguagem: Inglês

10.1038/ni.2454

1529-2916

Gaëlle Le Friec, Devon Sheppard, Pat Whiteman, Christian M. Karsten, Salley Al-Tilib Shamoun, Adam Laing, Laurence Bugeon, Margaret J. Dallman, Teresa Melchionna, Chandramouli Chillakuri, Richard Smith, Christian Drouet, Lionel Couzi, Véronique Frémeaux‐Bacchi, Jörg Köhl, Simon N. Waddington, James M. McDonnell, Alastair Baker, Penny A. Handford, Susan M. Lea, Claudia Kemper,

Adenosine and Purinergic Signaling

The complement receptor CD46 and the Notch-Jagged system are important for the differentiation of helper T cells. Kemper and colleagues demonstrate that Jagged1 is a physiological ligand for CD46 and is critical for the generation of T helper type 1 cells in humans. 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.