Recognition of secretory IgA by DC-SIGN: Implications for immune surveillance in the intestine

Abstract

Secretory IgA (SIgA), the predominant class of antibody in intestinal secretions, serves as the first line of defense against enteric infections. SIgA has also been proposed to function in immune surveillance, given that both SIgA and SIgA-antigen complexes are actively transported by Peyer’s patch M cells from the intestinal lumen to sub-epithelial dendritic cells (DCs). The goal of the present study was to identify the receptor(s) potentially utilized by mucosal DCs to recognize and internalize SIgA. We demonstrate that human colostral SIgA is recognized by purified recombinant human DC-specific ICAM-3 grabbing nonintegrin (DC-SIGN) in a solid phase binding assay, as well as by DC-SIGN ectopically expressed on the surface of Chinese hamster ovary (CHO-S) cells. The interaction between SIgA and DC-SIGN was specific, given that it was Ca2+-dependent and inhibited by mannan. Moreover, SIgA bound to, and was internalized by, endogenous DC-SIGN expressed on THP-1 cells following monocyte to macrophage-like cell differentiation by stimulation with phorbol ester and interleukin-4. These data identify DC-SIGN as a putative receptor for SIgA, and reveal a mechanism by which DCs could collaborate with M cells in immune surveillance at mucosal surfaces.

Secretory IgA Induces Tolerogenic Dendritic Cells through SIGNR1 Dampening Autoimmunity in Mice

“…SIGNR1 is a mouse homolog of DC-SIGN, a C-type lectin receptor that was recently described as a receptor for human SIgA on the cell surface of DCs (33). Our data suggest that SIGNR1 expressed by DCs serves as a SIgA-specific receptor, because dIgA and SC are not able to modulate the DC tolerogenic profile.…”

Delivery strategies to enhance oral vaccination against enteric infections

“…Examples of such DC-specific receptors include CD205/DEC205 and DC-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) [244]. DC-SIGN has also been shown to recognize SIgA which may present a novel targeting strategy [245]. Targeting of DCs can also be coupled to the delivery of TLR ligands as adjuvants which potently enhanced the ability of this approach to enhance Th1-mediated responses following subcutaneous vaccination [246].…”

The majority of intestinal IgA+ and IgG+ plasmablasts in the human gut are antigen-specific

“…Secretory IgA plays a major role in mediating immune exclusion of luminal antigens and homeostasis with the intestinal flora as well as protection against invading pathogens (5)(6)(7)(8)(9). Binding of secretory IgA to intestinal foreign antigens promotes the controlled antigen sampling of microbial and food antigens by microfold cells within the epithelial layer and helps to prevent attachment of microbes to the epithelium and clearance of microbes, which have breached the epithelial barrier (10)(11)(12)(13)(14). Recent evidence further suggests that IgA can induce downmodulation of proinflammatory epitopes on intestinal bacteria and thereby indirectly dampens the host's immune response (15).…”