Cells of Innate Immunity
The cells of the innate immune response are capable of recognizing microbes that share common surface receptor characteristics and in response initiate a broad spectrum of responses that target the invading microorganisms. The key cells of innate immunity include neutrophils, macrophages, DCs, NK cells, and intraepithelial lymphocytes.
Neutrophils and Macrophages
The leukocytes involved in the innate immune response are derived from myeloid stem cells and subdivided into two distinct groups based upon the presence or absence of specific staining granules in their cytoplasm. Leukocytes that contain granules are classified as granulocytes and include neutrophils, eosinophils, and basophils. Cells that lack granules are classified as agranulocytes and include lymphocytes, monocytes, and macrophages.
Neutrophils, which are named for their neutral-staining granules, are the most abundant granulocytes found in the body and make up approximately 55% of all white blood cells. They are also known as polymorphonuclear neutrophils (PMNs). They are phagocytic cells and are capable of ameboid-like movement. They function as early responder cells in innate immunity. They are rare in the tissues and in body cavities and lay predominantly dormant in the blood and bone marrow until they are needed in the immune response. Eosinophils have large coarse granules and normally com- prise only 1% to 4% of the total white cell count. In contrast to neutrophils, these cells do not ingest cellular debris but rather antigen–antibody complexes and viruses. They frequently become active in parasitic infections and allergic responses. Basophils make up less than 1% of the total white cell count and contain granules that release a multitude of substances including histamine and proteolytic enzymes. There function is not completely understood, but they are believed to play a role in allergy and parasitic infection as well.
The agranulocytes involved in innate immunity are part of the mononuclear phagocyte system (MPS) and include the monocytes and macrophages. Monocytes are the largest in size of all the white blood cells but make up only 3% to 7% of the total leukocyte count. They are released from the bone marrow into the bloodstream where they migrate into tissues and mature into macrophages and dendritic cells where they participate in the inflammatory response and phagocytize foreign substances and cellular debris. Macrophages have a long life span, reside in the tissues, and act as the first phagocyte that invading organisms encounter upon entering the host. Neutrophils and macrophages work in concert with each other and are crucial to the host’s defense against all intracellular and extracellular pathogens.
Macrophages are essential for the clearance of bacteria that breach the epithelial barrier in the intestine and other organ systems. They also have remarkable plasticity that allows them to efficiently respond to environmental signals and change their functional characteristics. This makes them more efficient phagocytic cells than the more abundant neutrophils. Once activated, these cells engulf and digest microbes that attach to their cell membrane. The ability of these phagocytic cells to initiate this response is dependent upon the recognition of pathogenic surface structures known as PAMPs or PRRs of which the TLRs have been the most extensively studied. Phagocytosis of invading microorganisms helps to limit the spread of infection until adaptive immune responses can become fully activated.
In addition to phagocytosis, macrophages and dendritic cells process and present antigens in the initiation of the immune response acting as a major initiator of the adaptive immune response. These cells secrete substances that initiate and coordinate the inflammatory response or activate lymphocytes. Macrophages can also remove antigen–antibody aggregates or, under the influence of T cells, they can destroy malignant host or virus-infected cells.
Dendritic cells (DCs) are specialized, bone marrow–derived leukocytes found in lymphoid tissue and are the bridge between the innate and adaptive immune systems. DCs take their name from the dendrites within the central nervous system because they have surface projections that give them a similar appearance. DCs are relatively rare cells that are found mainly in tissues exposed to external environments such as the respiratory and gastrointestinal systems. They are present primarily in an immature form that is available to directly sense pathogens, capture foreign agents, and transport them to secondary lymphoid tissues. Once activated DCs undergo a complex maturation process in order to function as key antigen-presenting cells (APCs) capable of initiating adaptive immunity. They are responsible for the processing and presentation of foreign antigens to the lymphocytes. DCs, like macrophages, also release several communication molecules that direct the nature of adaptive immune responses.
Natural Killer Cells and Intraepithelial Lymphocytes
NK cells and intraepithelial cells (IELs) are other cell types involved in the innate immune response. NK cells are so named because of their ability to spontaneously kill target organisms. Both types of cells rely on the recognition of specific PAMPs associated with the microorganism cell type.
NK cells are a heterogeneous population of innate lymphocytes that mediate spontaneous cytotoxicity against infected cells. They resemble large granular lymphocytes and are capable of killing some types of tumor and/or infected cells without previous exposure to surface antigens. NK cells were given their name because of their ability to mediate spontaneous cytotoxicity during both innate immune responses. However, they have been shown to play an equally important role in limiting the spread of infection and assisting in the development of adaptive immune responses through the production of cytokines.16 NK cells assist in dendritic cell maturation and innate immune control of viral infections. These cells are capable of directly killing host cell infected with intracellular (viral) or bacterial pathogenic organisms. They comprise approximately 10% to 15% of peripheral blood lymphocytes but do not bear T-cell receptors (TCR) or cell surface immunoglobulins (Igs). Two-cell surface molecules have been identified, CD16 and CD56, which are widely used to identify NK cell activity. CD16 serves as a receptor for the IgG molecule, which provides NK cells with the ability to lyse IgG-coated target cells.
NK cells can be divided into two main subsets based upon their ability to excrete proinflammatory cytokines. In addition, they differ in their expression of inhibitory versus activating receptors. Cells that express activating receptors (i.e., NKG2D) are induced in response to pathogen-infected or stressed cells, whereas the inhibitory receptors on NK cells recognize patterns (major histocompatibility complex [MHC]-I, lectins) on normal host cells and function to inhibit the action of the NK cells.16 This assures that only “foreign” cells are destroyed (see Fig. 13.2). In addition to their role as phagocytes, NK cells assist in T-cell polarization, DC maturation, and innate immune control of viral infection through the secretion of immune modulators and antiviral cytokines. Current research is investigating the utilization of these properties of NK cells for the development of vaccines that can modulate and direct the immune response through enhanced cytokine activity.