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
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.
