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Sci Signal. 2017 Oct 24;10(502). pii: eaah6163. doi: 10.1126/scisignal.aah6163.

TCR-stimulated changes in cell surface CD46 expression generate type 1 regulatory T cells.

Author information

1
Medical Research Council (MRC) Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.
2
Université Claude Bernard Lyon I, CNRS UMR 5310-INSERM U1217, F-69100 Lyon, France.
3
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
4
UK Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, UK.
5
Millipore (U.K.) Limited, Croxley Green Business Park, Watford, Hertfordshire WD18 8ZB, UK.
6
Medical Research Council (MRC) Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK. anne.astier@inserm.fr.
7
Centre de Physiopathologie Toulouse-Purpan, INSERM U1043, CNRS U5282, Université de Toulouse, Toulouse F-31300, France.

Abstract

A lack of regulatory T cell function is a critical factor in the pathogenesis of autoimmune diseases, such as multiple sclerosis (MS). Ligation of the complement regulatory protein CD46 facilitates the differentiation of T helper 1 (TH1) effector cells into interleukin-10 (IL-10)-secreting type 1 regulatory T cells (Tr1 cells), and this pathway is defective in MS patients. Cleavage of the ectodomain of CD46, which contains three N-glycosylation sites and multiple O-glycosylation sites, enables CD46 to activate T cells. We found that stimulation of the T cell receptor (TCR)-CD3 complex was associated with a reduction in the apparent molecular mass of CD46 in a manner that depended on O-glycosylation. CD3-stimulated changes in CD46 O-glycosylation status reduced CD46 processing and subsequent T cell signaling. During T cell activation, CD46 was recruited to the immune synapse in a manner that required its serine-, threonine-, and proline-rich (STP) region, which is rich in O-glycosylation sites. Recruitment of CD46 to the immune synapse switched T cells from producing the inflammatory cytokine interferon-γ (IFN-γ) to producing IL-10. Furthermore, CD4+ T cells isolated from MS patients did not exhibit a CD3-stimulated reduction in the mass of CD46 and thus showed increased amounts of cell surface CD46. Together, these data suggest a possible mechanism underlying the regulatory function of CD46 on T cells. Our findings may explain why this pathway is defective in patients with MS and provide insights into MS pathogenesis that could help to design future immunotherapies.

PMID:
29066539
DOI:
10.1126/scisignal.aah6163
[Indexed for MEDLINE]

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