Self- and Nonself-Recognition by C-Type Lectins on Dendritic Cells

Abstract

Dendritic cells (DCs) are highly efficient antigen-presenting cells (APCs) that collect antigen in body tissues and transport them to draining lymph nodes. Antigenic peptides are loaded onto major histocompatibility complex (MHC) molecules for presentation to naive T cells, resulting in the induction of cellular and humoral immune responses. DCs take up antigen through phagocytosis, pinocytosis, and endocytosis via different groups of receptor families, such as Fc receptors for antigen-antibody complexes, C-type lectin receptors (CLRs) for glycoproteins, and pattern recognition receptors, such as Toll-like receptors (TLRs), for microbial antigens. Uptake of antigen by CLRs leads to presentation of antigens on MHC class I and II molecules. DCs are well equipped to distinguish between self- and nonself-antigens by the variable expression of cell-surface receptors such as CLRs and TLRs. In the steady state, DCs are not immunologically quiescent but use their antigen-handling capacities to maintain peripheral tolerance. DCs are continuously sampling and presenting self- and harmless environmental proteins to silence immune activation. Uptake of self-components in the intestine and airways are good examples of sites where continuous presentation of self- and foreign antigens occurs without immune activation. In contrast, efficient antigen-specific immune activation occurs upon encounter of DCs with nonself-pathogens. Recognition of pathogens by DCs triggers specific receptors such as TLRs that result in DC maturation and subsequently immune activation. Here we discuss the concept that cross talk between TLRs and CLRs, differentially expressed by subsets of DCs, accounts for the different pathways to peripheral tolerance, such as deletion and suppression, and immune activation.

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

“…MR has also been described to mediate endocytosis of glycoproteins, such as self antigens in immature DC, and has been proposed together with other C-type lectins to play a role in the maintenance of tolerance [60]. Downregulation of C-type lectins after pathogen/TLRmediated activation of DC moves the spectrum of presented antigens from self to pathogenic antigens [60], and shifts the DC activity from being tolerogenic to being activating. The up-regulation of MR after activation of Aire -/-DC may, therefore, cause an efficient and inappropriate MR-mediated presentation of self antigens during immune responses towards pathogens.…”

Pathogen-Derived Oligosaccharides Improve Innate Immune Response to Intracellular Parasite Infection

“…Detection of pathogens and initiation of the innate immune response involve interactions between conserved motifs in the ligands as pathogen-associated molecular patterns and in pattern recognition receptors, including toll-like receptors (TLRs) and C-type lectin receptors expressed on host phagocytic cells. [1][2][3] Macrophages serve as a predominant phagocytic cell type specialized for identification, phagocytosis, and destruction of invading pathogens. Binding of microbial ligands to pattern recognition receptor triggers various crucial immune effector functions, including the production of proinflammatory cytokines.…”

Glycosylation-Dependent Interactions of C-Type Lectin DC-SIGN with Colorectal Tumor-Associated Lewis Glycans Impair the Function and Differentiation of Monocyte-Derived Dendritic Cells

“…4 On DCs two receptor families are involved in the recognition of pathogens and tumors: TLRs, which recognize common pathogen-associated molecular patterns, and C-type lectin receptors, which bind to glycan Ags (1). DCs are specialized APCs that recognize, acquire, process, and present Ags to naive resting T cells for the induction of an Ag-specific immune response (2)(3)(4).…”

“…DC-SIGN specifically recognizes glycoconjugates containing mannose (Man), N-acetylglucosamine (GlcNAc), and fucose (Fuc) on many pathogens and nonsialylated Lewis (Le) a /Le b (where Le a is Gal␤1-3(Fuc␣1-4)GlcNAc and Le b is Fuc␣1-2Gal␤1-3(Fuc␣1-4)GlcNAc; Gal, galactose) epitope structures in a Ca 2ϩ -dependent manner and has been shown to form tetramers (11). It is specifically expressed on DCs, MoDCs, and specialized macrophages in vitro and also on DC subsets in skin, mucosal tissues, tonsils, lymph nodes, and spleen in vivo (1). DC-SIGN functions as an adhesion receptor and mediates the binding and internalization of pathogens such as viruses (HIV and hepatitis C), bacteria (Mycobacterium), fungi, and parasites (1,13).…”