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Chapter 7 : C-Type Lectins: Multifaceted Receptors in Phagocyte Biology
Category: Microbial Genetics and Molecular Biology; Bacterial Pathogenesis
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This chapter focuses on those members of the C-type lectin family that contain a classical carbohydrate recognition domain (CRD) and are expressed and functional on phagocytic cells of the immune system, such as neutrophils, dendritic cells (DCs), and macrophages. C-type lectin receptors (CLRs) exist either as transmembrane proteins or as soluble proteins, but all contain one or more CRDs for binding to carbohydrate structures. Ca2+ is required for the interaction of carbohydrates with the CRD. Peptide fragments resulting from lysosomal degradation are eventually complexed onto major histocompatibility complex class II (MHC-II) molecules and exposed at the cell surface of antigen-presenting cells (APCs) to be inspected by T cells for self / nonself discrimination. A variety of molecules stimulate chemotaxis of innate immune cells, including microbial products such as the bacterial peptide formyl-methionyl-leucylphenylalanine (fMLP), activated complement (C5a), cytokines such as IL-8 and macrophage inhibitory protein 2, and bioactive lipids such as leukotriene B4. Recently, it was reported that SIGN-R1 associates with TLR4 to capture gramnegative bacteria and to facilitate signal transduction to activate innate macrophage responses. Antigen presentation upon engagement of a specific receptor is also likely to be affected by intracellular routing of the targeted receptor. Differences in their expression patterns on distinct DC subsets, their intracellular signaling cascades, as well as their intracellular routing will have consequences for the immunological outcome of in vivo DC therapy.
Examples of CLRs expressed at the cell surface or secreted by phagocytes. Type I CLRs (MMR and DEC-205) present an amino-terminal cysteine-rich repeat (S–S), a fibronectin type II repeat, and 8 to 10 CRDs, which bind ligand in a Ca2+-dependent manner. MMR binds ligands through CRD4 and -5. Type II CLRs have only one CRD at their carboxy-terminal extracellular domain. The cytoplasmic domains of transmembrane CLRs contain several conserved motifs essential for antigen uptake such as the tyrosine-based intracellular targeting motif, a triad of acidic amino acid residues, and a dileucine motif. Other type II CLRs contain additional signaling motifs such as ITIM, ITAM, and the proline-rich region. Collectins such as MBL, SPA, and SP-D are soluble CLRs that play important roles in innate immunity. They form large oligomers to enhance their affinity for carbohydrates exposed on microbial surfaces.
Overview of C-type lectins and their ligands