Journal
NATURE IMMUNOLOGY
Volume 13, Issue 12, Pages 1213-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.2454
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Funding
- Medical Research Council [G1002165]
- European Union
- Medical Research Council Centre for Transplantation (Guy's Hospital, King's College)
- Department of Health
- National Institute for Health Research Biomedical Research Centre
- Wellcome Trust [097928/A/08/Z]
- German Research Foundation [GRK1727 TP8, SFB/TR22 A21]
- European Research Council ('SomaBio')
- MRC [G1002165] Funding Source: UKRI
- Medical Research Council [G0600698B, MR/J006742/1, G1002165] Funding Source: researchfish
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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.
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