Cells Of The Immune System
The cells of the immune system can be divided broadly into two main
classes – myeloid and lymphoid
cells
Immune cells, which are
collectively called leukocytes (white blood cells), can be divided broadly into
myeloid and lymphoid subsets (Figure 1.7).
Myeloid cells,
which comprise the majority of the cells of the
innate immune system, include macrophages (and their monocyte
precursors), mast cells, dendritic cells, neutrophils,
basophils, and eosinophils. All myeloid cells have
some degree of phagocytic capacity (although basophils are very poorly
phagocytic compared to other myeloid cell types) and specialize in the
detection of pathogens via membrane or endosomal PRRs,
followed by engulfment and killing of infectious agents by means of a battery of destructive enzymes
contained within their intracellular granules.
Neutrophils are by far the most abundant leukocyte circulating in the bloodstream, comprising
well over 50% of leukocytes, and these cells are particularly adept at
phagocytosing and killing microbes. However, because of their
destructive potential, neutrophils are not permitted to exit the blood and
enter tissues until the necessity of their presence has been confirmed through
the actions of other cells of the innate immune system (especially macrophages
and mast cells), as well as soluble PRRs such as complement. As we shall see,
certain myeloid cells, such as macrophages and dendritic cells, have
particularly important roles in detecting and instigating immune responses,
as well as presenting the components of phagocytosed microbes to cells of the
lymphoid system. Broadly speaking, activated myeloid cells also have an
important function in escalating immune responses through the
secretion of multiple cytokines and chemokines as well as additional factors
that have powerful effects on local blood vessels.
The other major class of immune
cells, the lymphoid cells, comprise three main cell types, T‐lymphocytes,
B‐lymphocytes, and natural killer (NK) cells. T‐
and B‐lymphocytes are the central players in the adaptive immune system and
have the ability to generate highly specific cell surface receptors (T‐
and B‐cell receptors), through genetic recombination of a relatively limited
number of precursors for these receptors (discussed in detail in Chapters 4 and
5). T‐cell receptors (TCRs) and B‐cell receptors (also called antibodies) can
be generated that are exquisitely specific for particular molecular structures,
called antigens, and can fail to recognize related antigens that differ by only
a single amino acid. NK cells, although lymphocytes, play a major role within
the innate immune system, but these cells also police the presence of special
antigen‐presenting molecules (the aforementioned MHC molecules) that are
expressed on virtually all cells in the body and play a key role in the
operation of the adaptive immune system. NK cells use germline‐encoded
receptors (called NK receptors) that are distinct from the receptors of T‐ and
B‐cells and are endowed with the ability to kill cells that express abnormal MHC receptor
profiles, as well as other signs of infection.
Cells of the immune system originate in the bone marrow
All cells of the lymphoid and
myeloid lineages are derived from a common hematopoietic stem cell
progenitor in the bone mar- row (Figure 1.7). These stem cells, which
are self‐renewing, give rise to a common lymphoid progenitor as
well as a common myeloid progenitor, from which the various types
of lymphoid and myeloid cells differentiate (Figure 1.7). This process, called hematopoiesis,
is complex and takes place under the guidance of multiple factors within the
bone marrow, including stromal cells, the factors they produce and the
influence of the extracellular matrix. Indeed, the study of this process is a
whole research discipline in itself (hematology) and it has taken many years to
unravel the multiplicity of cues that dictate the production of the formed
elements of the blood. However, the basic scheme is that the various soluble
and membrane‐bound hematopoietic factors influence the differentiation of the
various myeloid and lymphoid cell types in a stepwise series of events that
involve the switching on of different transcriptional programs at
each stage of the hierarchy, such that immature precursor cells are guided
towards a variety of specific terminally differentiated cellular phenotypes
(monocytes, neutrophils, mast cells, etc.). This process can also be influenced
by factors external to the bone marrow (such as cytokines that are produced in
the context of immune responses), to ramp up the production of specific cell
types according to demand. Make no mistake, this is a large‐scale operation
with the average human requiring the production of almost 4 × 1011 leukocytes
(400 billion) per day. One of the reasons for this prodigious rate of cell
production is that many of the cells of the immune system, particularly the
granulocytes (neutrophils, basophils, and eosinophils), have half‐lives of only
a day or so. Thus, these cells require practically continuous replacement.
Upon differentiation to specific
mature lymphoid and myeloid cell types, the various leukocytes exit the bone
marrow and either circulate in the bloodstream until required or until they die
(granulocytes), or migrate to the peripheral tissues where they differentiate
further under the influence of tissue‐ specific factors (monocytes, mast cells,
dendritic cells), or undergo further selection and differentiation in
specialized compartments (e.g., T‐cells undergo further maturation and quality
control assessment in the thymus, see Chapter 10).
Myeloid cells comprise the majority of cells of the innate immune
system
Macrophages and mast cells
Macrophages and mast
cells are tissue‐resident cells and are frequently the first dedicated
immune cells to detect the presence of a pathogen (Figure 1.8). Both of these
cell types have an important role in sensing infection and in
amplifying immune responses, through the production of cytokines, chemokines,
and other soluble mediators (such as vasoactive amines and lipids) that have
effects on the local endothelium and facilitate the migration of other immune
cells (such as neutrophils) to the site
of an infection through recruitment of the latter from the blood. Mast cells in
particular have an important role in promoting vasodilation through production
of histamine, which has profound effects on the local vasculature. Macrophages
are derived from monocyte precursors that circulate in the blood-
stream for a number of hours before exiting the circulation to take up
residence in the tissues, where they undergo differentiation into specialized
tissue macrophages.
Tissue macrophages have
historically been given a variety of names based on their discovery through
histological analysis of different tissues. Thus we have Kupffer cells in the
liver, microglial cells in the brain, mesangial cells in the kidney, alveolar
cells in the lung, osteoclasts in the bone, as well as a number of other
macrophage types. Although macrophages do have tissue‐specific functions, all
tissue‐resident macrophages are highly phagocytic, can kill ingested microbes,
and can generate cytokines and chemokines upon engagement of their PRRs. We
will discuss the specific functions of macrophages and mast cells later in this
chapter.
Granulocytes
Neutrophils and
their close relatives, basophils and eosinophils,
which are collectively called granulocytes (Figure 1.9), are not
tissue‐resident but instead circulate in the bloodstream awaiting signals that
permit their entry into the peripheral tissues. Neutrophils, which are also
sometimes called polymorphonuclear neutrophils (PMNs), are by far the most
numerous of the three cell types, making up almost 97% of the granulocyte
population, and are highly phagocytic cells that are adept at hunting down and
capturing extracellular bacteria and yeast. Neutrophils arrive very rapidly at
the site of an infection, within a matter of a couple of hours after the first
signs of infection are detected. Indeed, very impressive swarms of these cells
migrate into infected tissues like a shoal of voracious piranha that can boast
neutrophil concentrations up to 100‐fold higher than are seen in the blood
circulation (Figure 1.10).
Basophils and eosinophils have
more specialized roles, coming into their own in
response to large parasites such as helminth worms, where they use the
constituents of their specialized granules (which contain histamine, DNAases,
lipases, peroxidase, proteases, and other cytotoxic proteins, such as major
basic protein) to attack and breach the tough outer cuticle of such worms.
Because worm parasites are multicellular, they cannot be phagocytosed by
macrophages or neutrophils but instead must be attacked with a bombardment
of destructive enzymes. This is achieved through release of the granule
contents of eosinophils and basophils (a process called degranulation)
directly onto the parasite, a process that carries a high risk of collateral
damage to host tissues. Basophils and eosinophils are also important sources of
cytokines, such as IL‐4, that have very important roles in shaping the nature
of adaptive immune responses (discussed later in Chapter 8).
Granulocytes have relatively
short half‐lives (amounting to a day or two), most likely related to the
powerful destructive enzymes that are
contained within their cytoplasmic granules. These are the riot police of the
immune system and, being relatively heavy‐handed, are only called into play
when there is clear evidence of an infection. Thus, the presence of
granulocytes in a tissue is clear evidence that an immune response is underway.
Egress of granulocytes from the circulation into tissues is facilitated by
changes in the local endothelium lining blood vessels, instigated by vasoactive
factors and cytokines/chemokines released by activated tissue macrophages and
mast cells, which alter the adhesive properties of the lining of blood vessels
closest to the site of infection. The latter changes, which include the
upregulation of adhesion molecules on the surface of the local blood vessels,
as well as the dilation of these vessels to permit the passage of cells and
other blood‐borne molecules more freely into the underlying tissue, facilitate
the extravasation of granulocytes from the blood into the
tissues.
Dendritic cells
Dendritic cells (DCs),
which were among the first immune cell types to be recognized, are a major
conduit between the innate and adaptive arms of the immune system. DCs have
characteristic highly elaborated morphology (Figure 1.8), with multiple long cellular processes (dendrites) that enable
them to maximize contact with their surroundings. Although most DCs are
tissue‐resident cells with phagocytic capacity similar to macrophages, their
primary role is not the destruction of microbes, but rather the sampling
of the tissue environment through continuous macropinocytosis and
phagocytosis of extracellular material. Upon detection and
internalization of a PAMP (and its associated microbe) through phagocytosis,
DCs undergo an important transition (called DC maturation) from a
highly phagocytic but inefficient antigen‐presenting cell into a lowly
phagocytic but highly migratory DC that is now equipped to present antigen
efficiently to T‐cells within local lymph nodes. We will return to this subject
later in this chapter, but the importance of the dendritic cell in the
induction of adaptive immunity cannot be overstated.
Lymphoid cells comprise the majority of the cells of the adaptive
immune system
T‐ and B‐lymphocytes
Lymphocytes constitute ~20–30% of
the leukocyte population and have a rather nondescript appearance (Figure
1.11), which belies their importance within the adaptive immune system.
As mentioned earlier, T‐ and
B‐lymphocytes are the central players in the adaptive immune system and have
the ability to generate highly specific cell surface receptors,
through genetic recombination of a relatively limited number of receptor pre-
cursors that are exquisitely specific for particular molecular structures,
called antigens. In principle, T‐cell receptors (TCRs) and B‐cell receptors
(BCRs, more commonly known as antibodies) can be generated to recognize
practically any molecular stucture (i.e., antigen), whether self or nonself derived.
However, as we shall see in Chapters 4 and 10, lymphocyte receptors undergo a
process of careful inspection after they have been generated to make sure that
those that recognize self antigens (or indeed fail to recognize anything useful
at all) are weeded out to ensure that the immune response does not become
targeted against self (a state called autoimmunity). T‐ and B‐lymphocytes also
have the ability to undergo clonal expansion, which enables those lymphocytes
that have generated useful (i.e., pathogen‐specific) TCRs and BCRs to undergo
rapid amplification, permitting the generation of large numbers of
pathogen‐specific T‐ and B‐cells within 5–7 days of the initiation of an immune
response. Specific T‐ and B‐cells can also persist in the body for many years
(called memory cells), which endows upon them the ability to
“remember” previous encounters with particular pathogens and to rapidly mount a
highly specific immune response upon a subsequent encounter with the same
pathogen.
T‐cells can be further subdivided
into three broad subsets: helper (Th), cytotoxic
(Tc), and regulatory (Treg) subsets that have roles in helping B‐cells to make
antibody (Th), killing virally‐infected cells
(Tc,) or policing the actions of other T‐cells (Treg). We will discuss T‐cells
and their different subsets extensively in Chapter 8.
Natural killer (NK) cells
NK cells, while also lymphocytes,
play a major role within the innate immune system, although these cells also
police the presence of special antigen‐presenting molecules (called MHC
molecules) that are expressed on virtually all cells in the body and play a key
role in the operation of the adaptive immune system. NK cells use germline‐encoded
receptors (NK receptors) that are distinct from the receptors of T‐ and B‐cells
and are endowed with the ability to kill cells that express abnormal MHC receptor
profiles. Viruses often interfere with MHC molecule expression as a strategy to
attempt to evade the adaptive immune response, which solicits the attentions of
NK cells and can lead to rapid killing of virally infected cells. NK cells also
have receptors for a particular antibody class (IgG) and can use this receptor
(CD16) to display antibody on their surface and in this way can seek out and
kill infected cells, a process called antibody‐dependent cellular
cytotoxicity. We will discuss NK cells more extensively later in this
chapter.
