This is discussed in more detail in the section that follows.
Figure 3.3. NK cell inhibitory receptors and killing.
PATTERN RECOGNITION: A MAJOR FEATURE OF INNATE IMMUNE RESPONSES
Now that we have outlined the origins and major characteristics of innate immune cells, we will discuss the sophisticated yet elegantly simple ways in which these cells initiate their host defense roles: pattern recognition. The underlying host defense mechanism associated with this arm of the immune system is the ability of innate cells and the specific soluble mediators they produce to recognize and respond to evolutionarily conserved microbial structures termed pathogen‐associated molecular patterns (PAMPs). Detection of PAMPs by innate immune cells occurs via soluble and cell‐associated germline‐encoded pattern recognition receptors (PRRs). It is important to note that this feature of innate immune recognition of pathogens differs markedly from recognition mechanisms associated with the adaptive immune system as illustrated in Figure 3.4.
As will be discussed in subsequent chapters, B and T lymphocytes (also called B and T cells, respectively) express somatically generated antigen‐specific receptors. Thus, these receptors are not germline encoded but rather the translational products of multiple genes that are pieced together by gene rearrangement that occurs during their development. Many PRRs are highly expressed on DCs—highly efficient APCs—where they can be located on the cell surface, in endocytic compartments, or the cytoplasm. Upon recognition of foreign antigen, particularly in the presence of PAMPs, DCs help to initiate an adaptive immune responses by B cells (which produce antigen‐specific antibody) and T cells (which express antigen‐specific T cell receptors). Adaptive responses take days to weeks to develop but last considerably longer (years) than innate responses, which are very rapid (minutes to hours) and last for a shorter time (days or weeks). In addition, in contrast with adaptive immune responses that ultimately result in the generation of clonally expanded, highly antigen‐specific memory B and T cells, activated innate immune cells do not expand or generate memory cells.
Figure 3.4. Comparison of specificity and cellular distribution of receptors used in innate and adaptive immunity.
Pattern Recognition Receptors
Most microorganisms encountered daily in the life of a healthy individual are detected and destroyed within minutes to hours by innate defense mechanisms. Mechanistically, innate immunity is carried out by nonspecific physical and chemical barriers (e.g., the skin, acid pH or the stomach), cellular barriers (e.g., phagocytes), and molecular pattern‐based reactions. This section describes the latter mechanism, which is used by a phylogenetically diverse set of species (fish, fruit flies, mammals) to enable host defense systems to detect the presence of foreign antigens that may do harm: the pattern recognition receptors. Based on their molecular structure, PRRs can be divided into multiple families, including TLRs, C‐type lectin receptors, NOD‐like receptors, and RIG‐I‐like receptors.
Toll‐Like Receptors.
A major class of pattern recognition receptors is the TLRs. The Toll gene family was originally discovered via its contribution to dorsoventral patterning in Drosophila melanogaster embryos. Later, studies showed that Toll genes encode proteins that play a critical role in the fly’s innate immune response to microbial infection. Further investigation then confirmed the existence of homologous proteins in mammals (TLRs) that can activate phagocytes and DCs to respond to pathogens. TLRs make up a large family of receptors and each recognizes specific microbial molecular patterns (Figure 3.5). Activation of cells expressing TLRs following receptor ligation also facilitates initiation of adaptive immune responses due to the production of proinflammatory cytokines by these activated cells. This phenomenon illustrates, yet again, the important functional and coordinated relationship that exists between the innate and adaptive immune systems.
Toll‐like receptors are expressed as membrane‐bound or cytoplasmic receptors that recognize a remarkably large number of PAMPs expressed by viral, bacterial, fungal and parasitic pathogen. TLR1, TLR2, TLR4, TLR5, and TLR6 are primarily expressed on the plasma membrane where they sense specific molecules on the surface of microbes. In contrast, TLR3, TLR7, TLR8, and TLR9 traffic from the endoplasmic reticulum to endolysosomal compartments where they recognize RNA and DNA. TLRs initiate signaling pathways through interactions with adaptor proteins, including MyD88 and Toll/interleukin‐1 receptor domain‐containing adaptor inducing IFN‐β (TRIF). Adaptor proteins function as flexible molecular scaffolds that mediate protein–protein and protein–lipid interactions in signal transduction pathways. When specific TLRs interact with adaptor proteins, signal transduction pathways are activated resulting in generation of mitogen‐associated protein kinases (MAPKs), nuclear factor κB (NF‐κB), and transcription of interferon regulatory factor (IRF)‐responsive genes.
Figure 3.5. Pattern‐recognition receptors called TLRs binding to molecules with specific pattern motifs expressed by various pathogens.
C‐Type Lectin Receptors.
C‐type lectin receptors (CLRs), which are membrane‐bound receptors, are a large family of receptors that bind to carbohydrates in a calcium‐dependent manner (by definition, all lectins bind to carbohydrates). They are involved in fungal recognition and the modulation of the innate immune response.
f‐Met‐Leu‐Phe Receptors.
A group of receptors specific for formylated peptides, such as N‐formylmethionine (fMet), are expressed at high levels on the membranes of polymorphonuclear and mononuclear phagocytes. fMet is specifically used for initiation of protein synthesis in bacteria. It is not used in cytosolic protein synthesis of eukaryotes. Synthetic formylated peptides have been shown to be chemotactic for phagocytes, leading to the concept of formylated peptides as PAMPs.
NOD‐Like Receptors.
NOD‐like receptors (NLRs) constitute a family of intracellular PRRs. The primary role of these cytoplasmic receptors is to recognize cytoplasmic PAMPs and/or the endogenous danger signal, thereby inducing immune responses. NLRs are characterized by a tripartite‐domain organization with a conserved nucleotide‐binding oligomerization domain (NOD) and leucine‐rich repeats (LRRs). Certain NLRs can assemble into a multiprotein complex called the inflammasome, which activates an enzyme called caspase‐1 that can cleave immature forms of certain cytokines, such as IL‐1 into active, mature cytokines (Figure 3.6). As the name implies, generation of inflammasomes is associated with
