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

Gaelle Le Friec, Devon Sheppard, Christian M. Karsten, Pat Whiteman, Salley Shamoun, Adam Laing, Simon N. Waddington, James M. McDonnell, Veronique Fremeaux-Bacchi, Lionel Couzi, Joerg Koehl, Alastair Baker, Penny A. Handford, Susan M. Lea, Claudia Kemper

Research output: Contribution to journalMeeting abstractpeer-review


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.
Original languageEnglish
Pages (from-to)1176-1176
Number of pages1
Issue number11
Publication statusPublished - Nov 2012


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