Summary RECEPTORS OF THE IMMUNE SYSTEM, PHAGOCYTIC CELLS, AND TOLERANCE

RECEPTORS OF THE IMMUNE SYSTEM, PHAGOCYTIC CELLS, AND TOLERANCE  Receptors of the innate immune system mediate a number of different functions.  Many are phagocytic receptors that stimulate ingestion of the pathogens they recognize.  Some are chemotactic receptors, such as the f-Met-Leu-Phe receptor, which binds the N-formylated peptides produced by bacteria, and guides neutrophils to sites of infection.  A third function is to induce effector molecules, that contribute to the induced responses of innate immunity, and molecules that influence the initiation and nature of subsequent adaptive immune response.  The surfaces of microorganisms typically bear repeating patterns of molecular structure.  The innate immune system recognizes such pathogens by means of receptors that bind features of these regular patterns; these receptors are sometimes known as pattern-recognition receptors/molecules (PRRs).  The mannan-binding lectin (MBL) that initiates the MB-lectin pathway of complement activation is an example of a PRR.  MBL is synthesized in the liver and released into circulation, along with a variety of other proteins from the collectin family (e.g., C1q).  For this receptor, pathogen recognition and discrimination from self is due to recognition of a particular orientation and spacing of certain sugar residues, which is found only on pathogenic microbes and not on host cells. Mannan-binding lectin (MBL) binds to patterns of carbohydrate groups in the correct spatial orientation. MBL is a member of the collectin family of proteins, composed of between two to six clusters of carbohydrate-binding lectin domains that interact with each other via a collagen-like domain. Within each cluster are three separate binding sites that have a fixed orientation relative to each other; all three sites can therefore only bind when their ligands—mannose and fucose residues in bacterial cell-wall polysaccharides—have the appropriate spacing.  The interaction of these soluble receptors with pathogens leads in turn to binding of the receptor-pathogen complex by phagocytes.  This occurs either through direct interaction with the pathogenbinding receptor, or through receptors for complement.  This promoting phagocytosis and killing of the bound pathogen, and the induction of other cellular responses.  Phagocytes are also equipped with several cell-surface receptors that recognize pathogen surfaces directly.  Among these is the macrophage mannose receptor (CD206).  This receptor is a cell-bound C-type lectin that binds certain sugar molecules found on the surface of many bacteria and some viruses, including the human immunodeficiency virus (HIV).  C-type lectin-like receptors (CLRs) represent a family of transmembrane pattern recognition receptors, expressed primarily by myeloid cells.  They recognize not only pathogen moieties for host defence, but also modified self-antigens such as damage-associated molecular patterns (DAMPs) released from dead cells.  The macrophage mannose receptor, like MBL, it is a multipronged molecule with several carbohydrate-recognition domains.  It is expressed predominantly by most tissue macrophages, dendritic cells and specific lymphatic or endothelial cells.  Because it is a transmembrane cell-surface receptor, it can function directly as a phagocytic receptor.  A second set of phagocytic receptors, called scavenger receptors(SRs), recognize certain anionic polymers and also acetylated low-density lipoproteins.  Some scavenger receptors recognize structures that are shielded by sialic acid on normal host cells.  These receptors are involved in the removal of old red blood cells that have lost sialic acid, as well as in the recognition and removal of pathogens.  They are a diverse group of receptors that also include CD36, CD68, SR class A, and SR class B, which mediate the uptake of oxidized lipoproteins into cells.  Another class of receptor is the Toll-like receptor (TLR).  TLRs appear not to recognize and bind pathogens directly, but rather are involved in signalling the appropriate response to different classes of pathogen.  In mammals, Toll-like receptor 4, or TLR-4, signals the presence of LPS by associating with CD14, the macrophage receptor for LPS.  TLR-4 is also involved in the immune response to at least one virus, respiratory syncytial virus, although in this case the nature of the stimulating ligand is not known.  Toll-like receptor, TLR-2, signals the presence of a different set of microbial constituents, which include the proteoglycans of grampositive bacteria, although how it recognizes these is not known.  The B cell receptor (BCR) is a membrane bound immunoglobulin (IgD and IgM).  T-cells also possess antigen recognition receptors that are referred to as T-cell receptors (TCRs).  The receptors that most T‐cells are equipped with cannot directly engage soluble antigens but instead “see” fragments of antigen that are immobilized within a narrow groove on the surface of MHC molecules.  MHC molecules bind to short 8–20 amino acid long peptide fragments that represent “quality control” samples of the proteins a cell is expressing at any given time, or what it has internalized through phagocytosis, depending on the type of MHC molecule.