The CD46-Jagged1 interaction is critical for human TH1 immunity.
Le Friec G., Sheppard D., Whiteman P., Karsten CM., Shamoun SA., Laing A., Bugeon L., Dallman MJ., Melchionna T., Chillakuri C., Smith RA., Drouet C., Couzi L., Fremeaux-Bacchi V., Köhl J., Waddington SN., McDonnell JM., Baker A., Handford PA., Lea SM., Kemper C.
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.