The CD46-Jagged1 interaction is critical for human TH1 immunity

Abstract

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 (TH1) 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 TH1 responses in vitro and in vivo suggesting that CD46-Jagged1 crosstalk is responsible for the recurrent infections in subpopulations of these patients.

Incomplete penetrance of CD46 mutation causing familial atypical hemolytic uremic syndrome

“…Disruption of immunomodulatory role of CD46 may cause susceptibility to infections or development of autoimmunity. CD46 is normally believed to engage with CD4+ T-cell receptor to induce Th1 cells and interact with extracellular ligand Jagged1 resulting in switch to interleukin-10 secreting regulatory T cells, facilitating B-cell activation [15]. T cells from a CD46-deficient patient were reported to have impaired IgG production [16], which may explain the known association between a subset of patients with homozygous CD46 deficiency and common variable immunodeficiency [6,10].…”

CHARGE syndrome: a review of the immunological aspects

“…48 The underlying immunological dysfunction was described in one paper as a diminished T-helper 1 response. 49 Patients with Pfeiffer syndrome (#MIM 101600, FGFR1) have overlapping features with CHARGE syndrome regarding cleft-lip and/or palate and hearing loss. 39 The immunological function in 12 patients with craniofacial malformation syndromes, including Pfeiffer syndrome, was studied by Scheuerle et al 50 Unfortunately, they did not specify the immunological dysfunction per syndrome.…”

A C3(H20) recycling pathway is a component of the intracellular complement system

“…The generation of C3a and C3b by human CD4 + T cells (8) is essential for the development of Th1 cell-mediated responses through autocrine stimulation of the C3aR and the complement membrane regulator CD46, respectively (9,10). To further define the mechanism governing C3a and C3b generation by CD4 + T cells, Liszewski et al (4) demonstrated that activation occurs inside the CD4 + T cell and that the processing into C3a and C3b is convertase independent, but cathepsin L (CTSL) dependent.…”