What cells are important in the innate immune system?
• Phagocytes contain PRRs and are critical effector cells of innate immunity by their ability to ingest microbes or cellular debris.
• Neutrophils are the first cells recruited to inflammation sites by various chemotactic signals (e.g., AMPs, N-formyl bacterial oligopeptide, C5a, leukotriene [LT] B4, IL-8). Neutrophils use at least two mechanisms to neutralize an invading microbe:
• Neutrophils phagocytose invading microbes opsonized by the innate immune system. The microbe is ingested into the phagosome which merges with intracellular granules containing microbicidal peptides, proteases, and highly reactive oxidizing agents generated by NADPH oxidase. The end result is microbial death. Note that even in the absence of infection, billions of neutrophils normally leave the bone marrow, circulate, enter tissues, and die each day. When they die, they undergo apoptosis and are processed by macrophages so they do not release their toxic constituents into normal tissues (efferocytosis). The macrophages that phagocytize the apoptotic neutrophils release antiinflammatory cytokines to maintain homeostasis.
• Neutrophil extracellular traps (NETs) are released from granules upon neutrophil activation. NETs contain complexes of proteins, histones, and DNA that bind and kill microbes extracellularly, independent of phagocytic uptake.
• Monocytes and macrophages: monocytes are the circulating precursors of macrophages; they differentiate into macrophages upon entry into specific tissues (e.g., Kupffer cells in liver). Macrophages can be activated by PRRs and Fc receptors (that bind the constant region of antibody). Macrophage activation results in the phagocytosis of microbes, processing of microbial antigen for presentation to lymphocytes to initiate the adaptive immune response, and secretion of over 100 proteins including cytokines (both proinflammatory and antiinflammatory) that mediate inflammation.
• Natural killer cells (NK): NK cells look like large granular lymphocytes and comprise 5% to 10% of the circulating lymphocyte population. They function as potent cytotoxic cells toward virally infected or malignant cells. They identify the target cells through the expression of killer cell immunoglobulin-like receptors (KIRs) that recognize MHC class I on healthy cells causing an inhibitory effect. Cells that are infected with viruses or are malignant upregulate stress ligands and downregulate their MHC class I receptors, which then cannot send an inhibitory signal via KIRs. Activating receptors on the NK cell include the characteristic cell surface markers CD16 (one type of Fc receptor) and CD56 as well as several PRRs. NK cells have granules with perforins and granzymes which are released upon NK cell activation to kill the target cell. Activated NK cells also secrete IFN-γ in addition to other cytokines. DCs recruit and activate NK cells by secreting type I IFNs, IL-12, and IL-18.
• Other cells exhibiting PRRs: epithelial cells express PRRs and can react to infection and secrete AMPs and IL-8 (CXCL8), which are neutrophil chemoattractants. Mast cells have PRRs and release TNFα and IL-8. They also produce inflammatory mediators (histamine, LTs, platelet-activating factor), proteases (tryptase, chymase), and defensins. Platelets express PRRs and can produce cytokines recruiting leukocytes to sites of tissue damage. They also release microparticles that may modulate the immune response. Eosinophils are specialized leukocytes whose granules contain numerous toxic products, including major basic protein, eosinophil peroxidase, and eosinophil cationic protein. These products are especially toxic to helminths. Activated eosinophils also produce large quantities of LTC 4 and transforming growth factor (TGF)-β that promote increased venular permeability and fibroblast-dependent fibrosis, respectively.
• DCs: these are “professional” antigen-presenting cells (APCs). They serve as a link between the innate and adaptive immune system. They are located in tissues in contact with the external environment including skin and mucous membranes of the respiratory, gastrointestinal, and genitourinary tracts. They are also present in lymphoid tissues and most solid organs. There are two major types of DCs: myeloid (mDCs) and plasmacytoid (pDCs). Most mDCs are derived from monocytes and a few from lymphoid cells. They display TLR2 and TLR4. The major cytokine that mDCs produce is IL-12, and it is the most important cell needed to activate naïve T cells. pDCs resemble plasma cells and comprise <1% of peripheral blood mononuclear cells. They display TLR7 and TLR9. They rapidly secrete large amounts of type I IFN (IFNα and IFNβ) following viral stimulation. Importantly, DCs can influence T-cell differentiation into Th1, Th2, Th17, and regulatory subtypes.
• Innate lymphoid cells (ILCs): these are innate immune cells derived from common lymphoid precursors. They respond to stress signals (alarmins), microbes (PAMPs), and cytokines in the environment by producing effector cytokines in patterns similar to T cells. There are three types: ILC1 cells produce IFNγ and play a role in cancer immunosurveillance; ILC2 cells produce Th2 cytokines (IL-4, IL-5, IL-13) and are important for antihelmintic immunity, immune regulation, and wound healing; ILC3 cells produce IL-17 and IL-22, which are important for mucosal immunity. ILC3 cells are found in lesional skin of patients with psoriasis.
