Cellular receptors that recognize carbohydrates on the surface of microbes facilitate the phagocytosis of the microbes and stimulate the secretion of cytokines that promote inflammation and subsequent adaptive immune responses (Table 1). These receptors belong to the C-type lectin family, so-called because they bind carbohydrates (hence lectins) in a Ca++-dependent manner (hence C-type). The C-type lectins are also called C-type lectin-like receptors or CLRs to parallel the nomenclature of TLRs and other pattern recognition receptors. These receptors are integral membrane proteins found on the surfaces of macrophages, DCs, and some tissue cells. Other lectins are soluble proteins in the blood and extracellular fluids. All of these molecules contain a conserved carbohydrate recognition domain. There are several types of plasma mem brane C-type lectins with specificities for different carbohydrates, including mannose, glucose, N-acetylglucosamine, and β-glucans. In general, these cell surface lectins recognize carbohydrate structures found on the cell walls of microorganisms but not mammalian cells. Some of these C-type lectin receptors function in the phagocytosis of microbes and others have signaling functions that induce protective responses of host cells to microbes.
Table1. C-Type Lectin-Like Receptors
• The mannose receptor (CD206) is expressed on macro phages, DCs, epithelial cells, and lymphatic endothelial cells and is involved in phagocytosis of various types of microbes. This receptor recognizes certain terminal sugars on microbial surface carbohydrates, including d-mannose, l-fucose, and N-acetyl-d-glucosamine. These terminal sugars are often present on the surface of microorganisms, whereas eukaryotic cell surface carbohydrates are most often terminated by galactose and sialic acid. Thus, the terminal sugars on microbes can be considered PAMPs. Signaling functions of the mannose receptor are not well described and the short cytoplasmic tail of the receptor contains no known signaling motifs.
• Dectins (DC-associated C-type lectins) include several different lectins encoded within a gene cluster on human chromosome 12, which also includes genes encoding NK cell receptors (discussed later). Dectins are expressed on DCs and macrophages and play important roles in anti fungal immunity, as well as in responses to certain bacteria. Dectin-1 (CD369) binds β-glucan, which is a major cell wall component of many fungal species and is required for immunity to various pathogenic fungi, including Candida, Aspergillus, and Pneumocystis. Dectin-2 and Mincle are two dectins that recognize high-mannose oligosaccharides on the hyphal form of some fungi and on bacteria. In response to binding of their ligands, these dectins induce signaling events in DCs and macrophages that activate a variety of immune functions. The cytoplasmic tail of Dectin-1 has an immunoreceptor tyrosine-based activation motif (ITAM), which engages tyrosine kinases that transduce signals leading to gene transcription. Dectin-2 and Mincle rely on an associated ITAM-bearing signaling partner protein called FcRγ. ITAMs are used by many different cell-activating receptors in the immune system; their mechanism of signaling will be discussed in Chapter 7. In response to ligand binding to Dectin-1, Dectin-2, or Mincle, DCs produce cytokines and other proteins that promote inflammation and enhance adaptive immune responses. Some of the induced cytokines promote the development of a type of effector T cell called Th17, which is particularly effective in defense against fungal and some bacterial infections.
• Langerin (CD207) and DC-SIGN (CD209) are two other lectins expressed on DCs, both of which bind mannose and have roles in immune responses to various microbes. Langerin is expressed by epidermal Langerhans cells and other subsets of DCs in the skin and other epithelial barriers. DC-SIGN is expressed on the majority of DCs as well as on macrophages and sinusoidal endothelial cells. DC-SIGN binds to envelope glycoproteins of the hepatitis C virus and HIV-1 and may play a pathogenic role in disseminating infection by these viruses.
