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

Gaëlle 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, Jörg Köhl, Simon N. Waddington, James M McDonnell, Alastair Baker, Penny A. Handford, Susan M. LeaClaudia Kemper

Research output: Contribution to journalArticleResearchpeer-review

91 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-γ (IFN-γ)-secreting effector T helper type 1 (TH1) 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-γ 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
Externally publishedYes

Cite this

Le Friec, G., Sheppard, D., Whiteman, P., Karsten, C. M., Shamoun, S. A. T., Laing, A., Bugeon, L., Dallman, M. J., Melchionna, T., Chillakuri, C., Smith, R. A., Drouet, C., Couzi, L., Fremeaux-Bacchi, V., Köhl, J., Waddington, S. N., McDonnell, J. M., Baker, A., Handford, P. A., ... Kemper, C. (2012). The CD46-Jagged1 interaction is critical for human T H 1 immunity. Nature Immunology, 13(12), 1213-1221. https://doi.org/10.1038/ni.2454