The CD46 and Jagged1 interaction is critical for human T helper 1 immunity

CD46 is a complement regulator with important immune-related roles. CD46 functions as a pathogen receptor and is a potent co-stimulator for the induction of interferon-γ (IFN-γ)-secreting T helper 1 (T(H)1) effector T cells and their subsequent switch into interleukin-10 (IL-10)-producing regulatory T cells. Here, we identify the Notch protein family member Jagged1 as a new physiological ligand for CD46. Further, CD46 regulates Notch receptors and ligands expression during T cell activation and disturbance of the CD46-Notch crosstalk impedes IFN-γ induction and IL-10 switching. Importantly, CD4(+) T cells from CD46-deficient patients and patients with hypomorphic Jagged1 mutations (Alagille Syndrome) fail to mount appropriate T(H)1 responses in vitro and in vivo suggesting that CD46-Jagged1 crosstalk is responsible for the recurrent infections in subpopulations of these patients.