The CD46-Jagged1 interaction is critical for human T(H)1 immunity

Gaelle Le Friec, Devon Sheppard, Pat Whiteman, Christian M. Karsten, Salley Al-Tilib Shamoun, Adam Laing, Laurence Bugeon, Margaret J. Dallman, Teresa Melchionna, Chandramouli Chillakuri, Richard A. Smith, Christian Drouet, Lionel Couzi, Veronique Fremeaux-Bacchi, Joerg Koehl, Simon N. Waddington, James M. McDonnell, Alastair Baker, Penny A. Handford, Susan M. LeaClaudia Kemper

Research output: Contribution to journalArticlepeer-review

135 Citations (Scopus)

Abstract

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-gamma (IFN-gamma)-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-gamma 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.

Original languageEnglish
Pages (from-to)1213-1221
Number of pages9
JournalNature Immunology
Volume13
Issue number12
DOIs
Publication statusPublished - Dec 2012

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