Identification of Jagged1 as a novel ligand for CD46: An interaction required for normal induction and regulation of human TH1 responses

CD46 is a complement regulator with important immune-related roles. CD46 functions as a pathogen receptor and is a potent co-stimulatory molecule on human CD4+T cells for the induction of IFN-g-producing TH1 cells and their subsequent switch into IL-10-secreting regulative cells. Here we show that CD46 not only modulates the expression of Notch protein family members but we also identify the Notch ligand Jagged1 as a new physiological ligand for CD46. In vitro experiments indicate that the CD46/Jagged1 interaction is crucial in the generation and regulation of human TH1 responses as interference in the crosstalk between the two systems hampers IFN-g induction and IL-10 switching. To investigate the biological relevance of this interaction, and because the murine CD46 homologue, Crry, does not recapitulate CD46 immune functions, we assessed the capacity of T cells from CD46- or Jagged-deficient patients for TH1 induction in vitro and in vivo. CD46 deficiency predisposes to atypical haemolytic uremic syndrome. However, a number of these patients also suffer from Common Variable Immunodeficiency and recurrent infections. Jagged1 mutations cause Alagille syndrome, a multisystem disorder involving primarily the liver, heart, eyes, face, and skeleton. Similarly, this disease is also often associated with recurrent infections and the underlying immune-related mechanisms are unexplored. We found that CD4+T cells from both patient groups had defective TH1 responses whilst the production of TH2 cytokines was normal or increased. Further, T cells from all patients revealed a marked deregulation of the IL-2 family receptor chains CD132 and CD127. Finally, these T cells were unable to induce a TH1 response in an in vivo humanized mouse model of graft versus host disease. Thus, this study highlights a novel interaction between the complement and Notch systems, at minimum critical for the control of TH1 responses during infection and possibly immune homeostasis.