Secretory IgA induces tolerogenic dendritic cells through SIGNR1 dampening autoimmunity in mice.
IgA plays ambivalent roles in the immune system. The balance between inhibitory and activating responses relies on the multimerization status of IgA and interaction with their cognate receptors. In mucosal sites, secretory IgA (SIgA) protects the host through immune-exclusion mechanisms, but its function in the bloodstream remains unknown. Using bone marrow-derived dendritic cells, we found that both human and mouse SIgA induce tolerogenic dendritic cells (DCs) following binding to specific ICAM-3 grabbing nonintegrin receptor 1. This interaction was dependent on Ca(2+) and mannose residues. SIgA-primed DCs (SIgA-DCs) are resistant to TLR-dependent maturation. Although SIgA-DCs fail to induce efficient proliferation and Th1 differentiation of naive responder T cells, they generate the expansion of regulatory T cells through IL-10 production. SIgA-DCs are highly potent in inhibiting autoimmune responses in mouse models of type 1 diabetes and multiple sclerosis. This discovery may offer new insights about mucosal-derived DC immunoregulation through SIgA opening new therapeutic approaches to autoimmune diseases.
INSERM U1016, Cochin Institute, Paris 75014, France.
Julien
J
Diana
Ivan C
IC
Moura
Céline
C
Vaugier
Aurélie
A
Gestin
Emilie
E
Tissandie
Lucie
L
Beaudoin
Blaise
B
Corthésy
Hakim
H
Hocini
Agnès
A
Lehuen
Renato C
RC
Monteiro
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007071:Immunoglobulin A, Secretory / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011956:Receptors, Cell Surface / Q000276:immunology*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D007071:Immunoglobulin A, Secretory; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin