ILCs, which include TCRγδ T cells, dendritic cells (DCs), macrophages, natural killer (NK) cells, and various subpopulations, are classified into four main categories (26.3). These cells differ from adaptive immune cells in that they lack antigen specificity for harmful agents and rely on the recognition of pathogen-associated molecular patterns (PAMPs) to differentiate self from non-self. To identify harmful pathogens, the body has developed a specialized recognition system that allows discrimination between self and non-self materials through the recognition of PAMPs present on the pathogens. This recognition occurs through pattern recognition receptors (PRRs) on host defense cells, specifically ILCs. PAMPs, such as peptidoglycans, lipopolysaccharides, and unmethylated 5'-C-phosphate-G-3' (CpG) DNA, bind to their corresponding PPRs on ILCs. The receptors are classified into two major types: toll-like receptors (TLRs), found mainly on cell surfaces, and nucleotide-oligomerization domain (NOD) receptors, located intracellularly within ILCs' cytoplasm. Both pathways activate nuclear factor Kβ (NFKβ), a transcription factor that triggers the release of proinflammatory cytokines and antiviral type I interferons (IFN-α and IFN-β). TLRs are a family of transmembrane proteins with different specificities for various pathogens. For instance, TLR-2 specifically recognizes lipoteichoic acids associated with gram-positive bacteria, while TLR-4 recognizes lipopolysaccharide (endotoxin), a product of gram-negative bacteria. In the lung, TLR-2 and TLR-4 are expressed by bronchial epithelial cells, macrophages, DCs, mast cells, eosinophils, and alveolar type II epithelial cells. TLRs dedicated to viral recognition include TLR-3 for double-stranded RNA viruses, and TLR-7 and TLR-8 for single-stranded RNA viruses. NK cells express TLR-3, TLR-7, and TLR-8, while plasmacytoid DCs, eosinophils, and B cells express TLR-7. TLRs are also expressed by various phagocytic cells and DCs in the lung and other mucosal tissues. Thus, in addition to classical phagocytic cells, bronchial and alveolar epithelial cells actively participate in host defense through the PAMP-PRR nexus.

What sets the specialized mucosal defense system apart is the remarkable ability of ILCs to respond immediately to pathogens, unlike the days or weeks required for a classical TCRαβ T cell adaptive immune response involving clonal expansion and memory. This fast response, combined with the lack of response to harmless substances, proves highly advantageous in mucosal tissues, which are often targeted by parasites and exposed to toxic chemicals. Furthermore, many ILCs exhibit plasticity, allowing them to alter their functionality to either a proinflammatory or regulatory (suppressive) phenotype in response to environmental factors, such as cytokines.
Innate lymphoid cells (ILCs) generally fall into four categories, TCRγδ T cells, dendritic cells (DCs), macrophages, natural killer (NK) cells, and subpopulations of each ( 26.3 ). ILCs are distinctively different from adaptive immune cells by their lack of “antigen” specificity for the offending agents and their ability to distinguish self from non-self through recognition of PAMPs present on the pathogens. Since most inhaled substances are nonpathogenic, the body has developed a specialized recognition system to identify harmful pathogenic substances and organisms. Rather than specific antigen recognition, this system enables discrimination of self from non-self material through the recognition of PAMPs on the pathogenic organisms/substances, which are then recognized by a family of receptors on host defense cells (i.e., ILCs) called pattern recognition receptors (PRRs). PAMPs are common distinguishing features on many pathogens and are composed of peptidoglycans, lipopolysaccharides, and unmethylated 5′-C-phosphate-G-3′ (CpG) DNA, which bind to their corresponding PPRs on ILCs. There are two major classifications for PRRs: toll-like receptors (TLRs), which are expressed mainly on cell surfaces, and nucleotide-oligomerization domain (NOD) receptors, which are expressed intracellularly in the cytoplasma of ILCs. Both of these pathways activate nuclear factor Kβ (NFKβ), a transcription factor, which stimulates release of proinflammatory cytokines, as well the antiviral type I interferons (IFN-α and IFN-β). The TLRs are a family of transmembrane proteins with different specificities for various pathogens. TLR-2 is specific for lipoteichoic acids associated with gram-positive bacteria, whereas TLR-4 is specific for lipopolysaccharide (endotoxin), a product of gram-negative bacteria. In the lung, bronchial epithelial cells, macrophages, DCs, mast cells, eosinophils, and alveolar type II epithelial cells express both TLR-2 and TLR-4. Other TLRs are specific for viruses: TLR-3 binds to double-stranded RNA viruses, and TLR-7 and TLR-8 bind to single-stranded RNA viruses. NK cells express TLR-3, TLR-7, and TLR-8 and plasmacytoid DCs, eosinophils, and B cells express TLR-7. A variety of phagocytic cells and DCs in the lung and other mucosal tissues also express TLRs. Thus in addition to classical phagocytic cells, bronchial and alveolar epithelial cells play active roles in host defense by means of the PAMP-PRR nexus.
Perhaps the most unique and intriguing aspect of this specialized mucosal defense system is the ability of ILCs to respond to pathogens immediately, as opposed to the days or weeks it takes to mount a classical TCRαβ T cell adaptive immune response with clonal expansion and memory. The fast response, and the lack thereof for innocuous substances, are highly advantageous in the mucosal tissues, which are common sites for parasitic invasion and toxic chemical exposure. In addition, many of the ILCs demonstrate plasticity, meaning that they can be induced by the environment (i.e., cytokines) to alter their functionality to either a proinflammatory or regulatory (suppressive) phentoype.