Key Notes
Receptors of the innate immune system interact with, and facilitate removal of, groups of organisms with similar structures. These pattern recognition receptors (PRR) recognize molecular patterns associated with certain groups of microbes, and act not only as a first line of defense against microbes, but also to prime the adaptive immune system.
This receptor is expressed on macrophages, dendritic cells and endothelial cells and recognizes a Ca2+-dependent, mannosyl/fucosyl pattern. It mediates phagocytosis of microbes and processing and presentation of microbial peptides on MHC Class II molecules, thus permitting induction of specific anti- microbial T and B cell responses.
Toll proteins or toll-like receptors (TLRs) are a family of germline encoded cell surface proteins that recognize and distinguish between molecular patterns of different groups of pathogens. They not only signal the presence of a
pathogen, but trigger the expression of co-stimulatory molecules and effector cytokines important in the development of adaptive immune responses.
This molecule is expressed on macrophages, binds LPS on Gram-negative bacteria, and facilitates destruction of the microbe and induction of secretion of cytokines involved in triggering adaptive immune responses.
Scavenger receptors on macrophages recognize carbohydrates or lipids in bacterial and yeast cell walls, as well as damaged, modified or apoptotic self cells, and mediate their removal.
Related topics
In addition to the soluble molecules of the innate immune system, an increasing number of cell surface receptors have been identified that not only act as a first line of defense against many infectious organisms, but also are important to the development of an adaptive immune response. These pattern recognition recep- tors (PRR) do not have the remarkable specificity of the T and B cell systems, but have developed over evolutionary time to recognize molecular patterns associated with certain kinds of microbes and to facilitate removal of groups of organisms with similar structures. Moreover, the receptors involved are expressed on a variety of cells some of which are critical to adaptive immunity.
These molecules include mannose receptors, CD14 and scavenger receptors, all expressed on macrophages (Fig. 1), as well as a recently identified family of Pattern
recognition receptors
Cells of the innate immune system (B1)
The microbial cosmos (H1) Pattern recognition
receptors
Mannose receptor
Toll-like receptors
CD14
Scavenger receptors
molecules, the Toll-like receptors (Table 1). It seems very likely that additional cell surface receptors important to innate immunity will also be found.
The mannose receptor is a 180 kDa transmembrane receptor expressed on macrophages, dendritic cells and subsets of endothelial cells. This receptor has eight carbohydrate recognition domains (CRDs), at least some of which have different pattern recognition motifs, making this one receptor fairly broad in the number and range of ligands it can recognize. Its Ca2+-dependent, mannosyl/
fucosyl recognition pattern permits it to interact with a variety of pathogens that enter through mucosal surfaces (Table 2). Because the mannose receptor is expressed on macrophages throughout the body, it is likely to be one of the first of the innate receptors to interact with microbes (Fig. 1). Furthermore, this receptor mediates phagocytosis and destruction of microbes even before the adaptive immune response is induced.
Mannose receptor
34 Section B – Cells and molecules of the innate immune system
Gram negative bacterium
LPS receptor (CD14)
Toll-like receptor Scavenger receptor Mannose receptor
Macrophage
Fig. 1. Macrophage expression of receptors involved in nonself recognition.
Table 1. Cell surface receptors recognizing nonself
Name Specificity Cellular location
Mannose receptors Mannosyl/fucosyl structures Macrophages, endothelial cells, dendritic cells
Toll-like receptors LPS, peptidoglycan, glucans, APCs, B cells, macrophages, teichoic acids, arabinomannans other
CD14 LPS Macrophages
Scavenger receptors Carbohydrates or lipids Macrophages, dendritic cells, endothelial cells
Table 2. Microorganisms that express ligands to which the mannose receptor binds Pseudomonas aeruginosa Mycobacterium tuberculosis
Candida albicans Pneumocystis carinii
Klebsiella pneumoniae Leishmania donovani
In addition to its role as a front-line receptor mediating destruction of a wide range of organisms, the mannose receptor represents an important direct link to the adaptive immune system. Thus, microbes bound by mannose receptor are internalized and degraded in endosomes. Peptides from the microbe are loaded on MHC class II molecules for display on the surface of these APCs so that T cells of the adaptive immune system can now recognize microbe determinants, thus permitting induction of microbe-specific T and B cell responses.
Toll-like receptors Toll proteins or Toll-like receptors (TLRs) are a family of closely related proteins that all have an extracellular leucine-rich repeat (LRR) domain and a cytoplasmic domain that mediates signal transduction of a variety of effector genes. One of these TLRs (TLR4) has been found to induce cytokine and co- stimulatory molecule expression on APCs. This also binds LPS and induces intracellular signaling. Furthermore, a molecule very similar to the TLRs, RP105, has been found on human B cells and dendritic cells. Cross-linking of this molecule on B cells induces expression of co-stimulatory molecules and proliferation.
Thus, different Toll proteins are able to recognize molecular patterns of different pathogens and to distinguish between different groups of pathogens.
In fact, it is now thought that different TLRs discriminate between the major molecular signatures of pathogens, including: peptidoglycan, teichoic acids (Gram-positive bacteria), LPS (Gram-negative bacteria), arabinomannans, and glucans. Of particular importance, these germline-encoded molecules of the innate immune system are not only able to signal the presence of a pathogen, but trigger expression of co-stimulatory molecules and effector cytokines, and in so doing prepare the cell for its involvement in the development of the adaptive immune response.
CD14 CD14 is a phosphoinositolglycan-linked cell surface receptor on macrophages (Table 1) that binds to lipopolysaccharide (LPS), a unique bacterial surface struc- ture found only in the cell walls of Gram-negative bacteria, e.g. E. coli, Neisseria, Salmonella. The core carbohydrate and lipid A of LPS are virtually the same for these microbes and are the target for binding by CD14. Binding of LPS on a Gram-negative bacteria to macrophage CD14 and TLR4 facilitates destruction of the microbe as well as induction of secretion of various cytokines involved in triggering a wide array of immune responses.
SR are a group of transmembrane cell surface molecules that mediate binding and internalization (endocytosis) of microbes (both Gram-negative and Gram- positive) as well as certain modified, damaged or apoptotic self cells. These molecules are expressed on macrophages and dendritic cells as well as on some endothelial cells and have specificity for polyanionic molecules and the cells with which they are associated. At least seven different SR that may interact with microbes have been identified, including SR-A I and II, MARCO, SR-CL I and II, dSR-C1 and LOX-1. Of note, SR-A has apparent specificity for the lipid A component of lipopolysaccharide and of lipoteichoic acid which are associ- ated with bacteria. Another SR, LOX-1 not only binds oxidized LDL and there- fore appears to play a role in atherogenesis, but can also recognize certain microbes (e.g. S. aureus andE. coli) and may be important in innate immunity.
Scavenger receptors (SR)
B3 – Recognition of microbes by the innate immune system 35
Section B – Cells and molecules of the innate immune system