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| An
Overview of the Immune System, Part One: © California Association
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|
An Overview
of the Immune System, Part One:
The Cells and Cell Surface Molecules
| Preface/Author’s Note As an undergraduate student in Clinical Science at San Francisco State University, I had the privilege of being introduced to the field of immunology by Dr. Janis Kuby. It was her skill and enthusiasm, as both a professor and an immunologist, that led to my pursuit of a Ph.D. in immunology many years later. When I began teaching an undergraduate immunology course, I was delighted to discover that she had written an immunology textbook which reflected both her command and her love of the subject. Sadly, Dr. Kuby lost a long-standing battle with cancer within weeks of completing the third edition of her text in 1997. It is a testament to the quality of the original textbook that it has been continued in Janis Kuby’s name by a trio of authors, with the release of its sixth edition in 2006. It is with pride that I highly recommend Kuby Immunology and use it as one of my primary references. Janis Kuby will never be forgotten by anyone who has ever had the benefit of her knowledge and love of immunology, either face-to-face, or through her writing. With deep gratitude, I dedicate these immunology study courses to Dr. Kuby’s memory. |
ABSTRACT/MEASURABLE OBJECTIVES:
Immunology is becoming an integral part of clinical medicine and therefore, an increasingly important aspect of clinical laboratory work. This is the first of two courses designed to refresh and update the clinical laboratory scientist’s basic understanding of this rapidly changing field. This course provides a description of the innate (non-specific) immune system, and a review of the white blood cells that contribute to both innate and adaptive (antigen-specific) immune responses. This includes a discussion of critical cell-surface molecules, and the markers used to identify different cell types.
OBJECTIVES:
Upon completion of this course, the reader will be able to:
- List physical and chemical barriers of the innate immune system
- Identify the white blood cells that are not antigen-specific
- Describe immunologic functions of the three antigen-specific lymphocyelymphocyte subsets
- List the differences in antigen presentation to CD4+ and CD8+ T cells
- Identify cells of the immune system utilizing CD nomenclature
LIST OF FREQUENTLY-USED ABBREVIATIONS:
| TLRs | Toll-like receptors | WBCs | white blood cells |
| APC | antigen-presenting cell | MHC | major histocompatibility complex |
| NK | natural killer | µL | microliter |
| CTL | cytotoxic T lymphocyte | TH | T helper cell |
| TCR | T cell receptor | CD | cluster of differentiation |
INTRODUCTION:
The immune system is not a single discrete organ or collection
of tissues, located in one or a few anatomic sites. In fact, it could be considered
two collaborative systems: the innate immune system that reacts in a relatively
non-specific manner, and the adaptive (or acquired) immune system, capable of
incredibly specific recognition and response (1). These immune systems are composed
of a variety of tissues and cells types, both fixed and mobile throughout the
body, that work together, first to try to prevent the entry of pathogens and/or
foreign material (known as antigens) into the body. Failing that, the immune
systems spring into action to recognize and respond to the presence of antigens
in order to eliminate or neutralize them, especially those associated with microbial
pathogens.
I. The Innate Immune System
Innate
immunity is an ancient evolutionary feature, with some form found in all multicellular
plants and animals (1). The innate immune system consists to a great extentmainly
of components that are pre-existing and ready to act prior to exposure to antigens.
It is designed to prevent the entry of and/or rapidly eliminate antigens such
as pathogens, toxins, or other foreign materials. Using a combination of soluble
antimicrobial molecules, cells, and membrane-bound receptors on the surface
of cells, the innate immune system can initiate an instantaneous attack on antigens.
The innate system is capable of distinguishing between self and foreign molecules,
by utilizing cellular and molecular components that recognize classes of molecules
unique to microbes. Unlike the more sophisticated (and complicated) adaptive
immune system, the innate system is not able to distinguish the more subtle
differences between among different foreign antigens or to remember a previous
exposure to the same antigen(s). It acts in the first few hours and days of
an exposure,, before the activation of the adaptive immune system. In general,
the innate immune system can deal with most antigen exposures without ever calling
upon or activating the antigen-specific adaptive immune system. Innate immunity
is considered, therefore, to be the first line of defense. If an antigen exposure
is sufficiently large, and/or involves a more virulent pathogen, the innate
immune system then serves as a trigger for the adaptive immune system.
The first defenses of innate immunity are a collection of physical
and chemical barriers (1). Physical barriers include the intact skin,, and mucous
production, and ciliary action on mucous membranes throughout the body. Chemical
barriers range from the acidity of the gastrointestinal and genitourinary tracts
to a host of molecules secreted by cells and tissues with specialized activity
against microbial and/or other antigens. These include a) enzymes in saliva
and tears such as lysozyme; b), an antibacterial protein produced by the skin
called psoriasin, which prevents bacterial colonization (especially by
E. coli); , and c) naturally-occurring anti-viral proteins known as
interferons. One of the best-known chemical barriers is the complement cascade
(the bane of many a clinical laboratory student), which acts in a sequential
fashion to convert inactive circulating proteins to active molecules. These
molecules have the ability to damage the cellular membranes of certain types
of pathogens and/or facilitate pathogen/antigen clearance by inducing inflammation
and enhancing phagocytosis (as described below).
If an antigen is able to breach
the physical and/or chemical barriers of the innate immune system, it encounters
the next line of defense, namely, the white blood cells (WBCs) within the blood
and tissues of the body. Some kinds of WBCs contribute to innate immunity by
recognizing patterns of molecules that are found on frequently-encountered pathogens,
but are typically never expressed on the cells and tissues of humans (or other
multicellular organisms) (1). The cells utilize sensors or receptors on their
cell surfaces, that recognize particular types of structures on microbial
species. The microbial structures recognized by innate WBCs, such as components
of bacterial cell walls, are usually necessary for survival of microbes, and
therefore, tend to remain constant across species and across time. The most
important group of innate system receptors are the Toll-like receptors (TLRs),
that were discovered and characterized as part of the innate immune system
in humans in the late 1990s. TLRs recognize a broad variety of viruses, bacteria,
fungi, and some protozoa by binding to molecules such as flagellin, lipopolysaccharide
(LPS) in gram-negative bacterial cell walls, and zymosan in the cell walls of
fungi. TLRs are also capable of recognizing molecular structures such as a particular
sequence found in the genetic material of bacteria (CpG), that lacks chemical
modification by methylation (a hallmark of microbial DNA), or the single- or
double-stranded ribonucleic acid (RNA) associated with viral infections. The
engagement of TLRs by the appropriate microbial molecules makes WBCs more efficient
in processing, killing, and clearing pathogens. The binding of TLRs to microbial
structures also contributes to the development of inflammation, and stimulates
the production of signaling molecules known as cytokines that affect the behavior
of WBCs involved in both innate and adaptive immune responses.
II. The WBCs of the immune system
WBCs are an essential part of both innate and adaptive immune
responses. In order to understand the workings of the immune system as a whole,
it is necessary to be familiar with the different types of WBCs and the role(s)
each plays in one or both of these immune responses.
WBCs circulate not only in the blood, but also through the lymph
nodes via the lymphatic system. In addition, they are widely distributed throughout
the tissues of the body, and in many cases, move freely between blood, lymph,
and tissue compartments. Because of its the ease of blood collectionin collection
compared to lymph and/or tissue collection, WBCs were first observed and characterized
in the peripheral blood, and it remains the routine sample of choice for evaluation
of WBCs. In such a peripheral blood sample from a normal individual, the expected
WBC count would be 3500 to 9500 cells per microliter (µ?L) of blood (Table 1).
If blood is collected in an untreated glass tube, it will clot,
trapping and/or lysing the WBCs in the clotting process. Therefore, if a blood
sample is being collected for examination of WBCs, it must be treated with anticoagulants
to prevent clotting and to enable the blood to remain liquid. When a tube of
anticoagulated blood is allowed to separate, either by low speed centrifugation
or by settling out due to gravity, it will segregate into the three basic components
of blood: plasma, WBCs, and red blood cells (Figure 1).
Plasma, the liquid portion of the blood, will be at the top of
the tube. Plasma contains all of the nutrients, vitamins, minerals, etc., as
well as the wastes, thatwastes that circulate in the blood. Platelets, the very
small cellular fragments that are essential to the clotting process, usually
remain suspended in the plasma as well. The red blood cells will be at the bottom
of the tube. Their function is to carry oxygen to the tissues and carbon dioxide
back to the lungs. In between the plasma and the red blood cells, in a very
thin layer often referred to as the "buffy coat,", will be the WBCs. (The thickness
of this layer is exaggerated in Figure 1 simply to make it visible in the drawing.)
Classically, the WBCs have been categorized according to morphologic
differences visible in stained cells under a light microscope. The initial subdivision
of WBCs in Figure 1 reflects this by separating cells into lymphocytes and monocytes
(mononuclear cells) and granulocytes (multinuclear or polymorphonuclear cells).
However, for the purposes of examining functions of the different WBCs in the
immune system, it is useful to discuss them in terms of their ability to participate
in innate and/or adaptive (antigen-specific) immune responses.
Microbial pathogens and other foreign materials are typically relatively large
and complex structures, composed of many different smaller antigens. Individual
antigens have distinctive, three-dimensional shapes that can be physically distinguished
from one another by the immune system. However, not all WBCs are equipped to
make such an antigen-specific distinction. As described above, the WBCs involved
in innate responses can distinguish between foreign and self-antigen, but cannot
recognize differences between individual antigens. Other types of WBCs are remarkably
specific, capable of recognizing and responding to individual antigens, which
gives rise to adaptive or antigen-specific immune responses. The following review
of the WBCs will consider the different cell types starting with the less-specific
cells (at the bottom of Figure 1) and progressing to the antigen-specific cells
(at the top of Figure 1).
Granulocytes
Granulocytes are the only WBCs with nuclei that have multiple
lobes, and so they are described as multinuclear or polymorphonuclear cells.
As their name implies, they contain granules in their cytoplasm. The three different
types of granulocytes are distinguished by the staining properties of these
granules-neutral, acidic or eosinic, or basic. From an immunologic perspective,
granulocytes differ not only in appearance, but in function.
Neutrophils (also known as polymorphonuclear cells, PMNs, or polys)
are the most numerous type of WBC, making up 50-70% of the circulating WBC in
a normal individual (1). They have distinctly multilobed or segmented nuclei
(under normal circumstances) and the granules they contain are neutral-staining.
Neutrophils are a major part of the innate immneimmune response, utilizing TLRs
on their surface to broadly recognize pathogens and other foreign materials
which need to be cleared from the body. They will attempt to engulf and take
up or phagocytose any and all types of foreign material and organisms with which
they come in contact, as well as debris (such as dead and dying cells). One
could think of neutrophils as the vacuum cleaners of the body-they are not capable
of discriminating between individual antigens, and therefore, they will always
respond by trying to pick up up and dispose of any offending material which
they encounter. and dispose of it. The phagocytic activity of neutrophils is
greatly enhanced by the binding of active complement components and/or antigen-specific
antibodies to pathogens/antigens, a process known as opsonization. Opsonization
by molecules produced during both innate (complement) and antigen-specific (antibody)
immune responses is just one example of how the two types of responses can affect
one another.
Once a neutrophil has successfully phagocytosed an antigen, it
will kill and/or digest that pathogen/antigen inside the cell. This is accomplished
by using a wide variety of enzymes such as peroxidase and lysozyme which are
stored in its granules, and highly active molecules such as reactive oxygen
and nitrogen intermediates which are produced following the process of phagocytosis.
In addition, neutrophils are rich in naturally-occuringoccurring antimicrobial
peptides known as defensins, which rapidly kill a wide variety of microbes.
Once the antigens have been degraded within the neutrophil, the resulting bits
and pieces are released back into the bloodstream (or lymph fluid), where they
are eventually filtered out by the kidneys.
After being produced in the bone marrow, neutrophils circulate
in the blood only briefly (7-10 hours), thenand then migrate into the tissues
where they remain viable for 1-3 days. They are attracted to sites of injury
and/or inflammation by chemotactic factors, that are initially released
as a result of tissue damage and clotting. The neutrophils will move through
the blood and/or tissue toward the source of the chemotactic factors, and are
usually the first cells to arrive at an inflammatory site. In fact, the white
pus which develops at a wound site is composed primarily of neutrophils that
have migrated to the site. By virtue of their sheer numbers, the neutrophils
will almost always be the first to encounter invaders. They are, therefore,
a critical first line of defense against invading pathogens and antigens,..
If the dose of antigen is low, the neutrophils alone may be sufficient to clear
the antigen from the body, without any further need for a response by antigen-specific
WBCs.
Eosinophils are a much rarer cell type, typically making up 1-3 % of circulating
WBC (1). They derive their name from the acidic or eosinic staining of their
granules. Eosinophils are non-specific phagocytic cells like the neutrophils,
but less is known about their function. Eosinophilia, or increased numbers of
eosinophils, is characteristic of parasitic infections, and there is evidence
that this cell type is involved in immune responses to parasites. Eosinophilia
may also be observed in highly allergic or atopic individuals.
Basophils are
the rarest of the granulocytes, making up less than 1% of the circulating WBC.
They are non-phagocytic cells, and are easily recognized by the heavy purple
or blue basic staining of their cytoplasmic granules, that frequently
obscure the nucleus. These granules are the key to the function of basophils,
as they contain histamine and other highly biologically active molecules that
are released during allergic responses. Like neutrophils and eosinophils, the
basophils themselves are not antigen-specific. Their ultimate function, however,
is dependent on interactions with antibodies of the IgE class which are antigen-specific.
When coated with IgE antibodies specific for antigens that induce allergic responses
(known as allergens), basophils will release the potent contents of their granules
when IgE binds to the relevant allergen. It is these cells, therefore, that
are responsible for the all-too-familiar allergy symptoms of hayfeverhay fever,
hives, and asthma, as well as the severe, life-threatening anaphylactic type
of allergic responses. A similar cell found in the tissues rather than circulating
in the blood,blood is known as a mast cell.
Monocytes/macrophages
Mononuclear cells are easy to distinguish from granulocytes on
the basis of morphology, and can be subdivided into monocytes and lymphocytes.
These two types of mononuclear cells have subtle differences in their morphology,
but have enormous differences in their immunologic function. These differences
are reflected in the placement of monocytes in Figure 1. Monocytes are phagocytic
cells that, like neutrophils, are very important in innate responses, but do
not have the ability to discriminate between antigens, as do some of the lymphocytes.
Monocytes are placed below the lymphocytes because they lack antigen-specific
recognition, but are placed above the granulocytes due to additional functions
that help them serve as a bridge between innate and adaptive immune responses.
Monocytes typically represent 1-6% of the WBCs in the blood, where
they circulate for about eight hours after being produced in the bone marrow
(1). Following that time, they migrate into the tissues, where they are called
macrophages. They may remain mobile within the tissue, or they may become fixed,
where they take on a particular function within a given tissue. Many types of
fixed macrophages have been recognized and given special names, e.g., Kupffer
cells of the liver, alveolar macrophages in the lung, and microglial cells in
the brain.
Like neutrophils, macrophages are phagocytic cells that utilize
TLRs on their cell surface to recognize antigens and/or pathogens. Following
stimulation via the TLRs, these cells become activated, resulting in increased
phagocytosis and a greater ability to kill pathogens and eliminate antigenseliminate
antigens, utilizing many of the same mechanisms as neutrophils. However, unlike
neutrophils, phagocytosis by macrophages also triggers a cascade of protein
production that serves additional functions. These include enzymes that
aid in enhanced killing and/or digestion, and complement components that participate
in inflammatory reactions. In addition, activated macrophages produce and secrete
a class of proteins known as cytokines, whichthat play important roles in both
innate and adaptive immune responses.
Cytokines are protein messenger molecules that send signals or
messages between cells (1, 2). The term "cytokine" is derived from "cyto", meaning
"cell", and "-kine", which indicates movement (as in the word "kinetic"). Therefore,
"cytokine" is a broad term that refers to all proteins that send messages from
one cell to another, regardless of cell type or the action of the cytokine.
There are other names that have been given to subgroups of cytokines based on
cell types and/or function, such as interleukins ("between leukocytes") and
interferons (which interfere with virus replication).
Activated macrophages secrete a very characteristic pattern of
cytokines, sometimes referred to as monokines. These secreted proteins diffuse
into the blood or lymph fluid, and send messages to nearby cells. Some of the
cytokines are chemotactic factors (also known as chemokines) that attract neutrophils
to a site of inflammation. Certain cytokines secreted by macrophages exert their
effects at great distances, like hormones, inducing fever by acting on the hypothalamus.
Cytokines secreted by activated macrophages also help to recruit, stimulate
and/or activate antigen-specific lymphocytes, aiding in the initiation of adaptive
immune responses. Through its secretion of proteins, especially cytokines, the
macrophage serves as a bridge between innate and adaptive responses...
There is yet another function of activated macrophages that positions
these cells as critical links between innate and adaptive immunity. When a macrophage
digests antigen that has been brought into the cell non-specifically by phagocytosis,
it does not completely eliminate the digested antigen. Rather, it retains small
fragments of antigen that are then transported to and displayed on the surface
of the cell. The digested antigen is presented on the macrophage cell surface
to other WBCs that are capable of recognizing and responding to it. This antigen
presentation is absolutely required to initiate an antigen-specific immune response.
So, although the macrophage itself is not antigen-specific, it can play an essential
role in the initiation of antigen-specific responses by serving as an antigen-presenting
cell (APC).
When antigens are presented on the surface of a macrophage, they
are physically-associated with major histocompatabilityhistocompatibility complex
(MHC) molecules. These molecules, which which in humans are referred to as human
leukocyte antigens (HLA) or transplantation antigens, are the molecules that
the immune system uses to distinguish self cells and/or tissues from non-self
or foreign cells. Every individual has a collection (or complex) of MHC molecules
which are identical throughout his or her body; however, one person's collection
of MHC molecules is going to be distinctively different from those on most other
individuals' cells and tissues. Therefore, it is the collection of MHC molecules
found within each individual that defines what is self or non-self. During embryonic
development, the immune system learns to recognize a self cell by interacting
with the MHC molecules expressed on cells throughout the body. At the same time,
exposure to self antigens trains the developing immune system to ignore self
components and mount immune responses only against foreign antigens. In a normal
individual, these processes result in antigen-specific WBCs that will only respond
to an antigen that is both foreign and properly presented in association with
self-MHC molecules. If the immune systems failssystems fail to discriminate
between self antigens and foreign antigens, then an autoimmune condition can
develop. This is one of many systems of checks and balance within the immune
system, to ensure that only appropriate responses are mounted. Therefore, the
ability of macrophages to present antigen in association with MHC molecules
is absolutely critical to their ability to act as antigen-presenting cells.
Macrophages are not the only innate immune cells that can present antigen (1).
There is another population of WBCs, called dendritic cells, that are non-specific,
yet highly-efficient APCs. Immature dendritic cells are activated via TLRs and
other cell surface receptors, resulting in high levels of MHC molecules on their
cell surfaces. As with other innate cells, antigens are phagocytosed and degraded,
but dendritic cells then migrate to lymphoid tissues (such as lymph nodes),
where they are very potent APCs for most kinds of antigen-specific T lymphocytes.
They are produced in the bone marrow from the same myeloid precursor as monocytes
and macrophages, but it is unclear whether they are derived from macrophages
or are a separate but parallel lineage of cells. Dendritic cells are not shown
on Figure 1, as they are extremely rare in the peripheral blood (0.1% of circulating
WBCs). Dendritic cells are more commonly found in the thymus, lymph nodes, and
other immune system tissues, in most organs, and in the skin, where they are
called Langerhans cells.
Lymphocytes
The remaining WBCs in Figure 1 to be discussed are the other type
of mononuclear cells, the lymphocytes. Lymphocytes account for 20-40% of the
total WBCs circulating in the blood (1), with a normal lymphocyte count expected
to be approximately 1100 to 2800 cells/µ?L (Table 1). However, the lymphocytes
in the peripheral blood represent only 1% of all lymphocytes, as the remaining
99% are found in the lymph system, circulating in the lymph fluid and residing
in regional lymph nodes and other lymphatic tissue such as Peyer's patches in
the intestine and tonsils in the throat. Because such a large percentage of
these WBCs is spread throughout the body, the immune system is often thought
of as a relatively small organ system. It is estimated, however, that in an
average human being, there are 1010 - 1012 lymphocytes distributed throughout
the body, which collectively have a cellular mass equivalent to the liver or
brain.
There are three different types of lymphocytes, all of which are
non-phagocytic, mononuclear, mononuclear WBCs. They are indistinguishable by
morphology alone, and so have historically been identified by differences in
cellular function. One of the three, the natural killer cell, although it is
a lymphocyte by hematologic lineage, is an innate non-specific cell. Hence,
it is shown in Figure 1 below the other two types of lymphocytes, and will be
discussed first.
Natural killer (NK) cells typically make up approximately 5-10
% of the circulating lymphocyte population (1), but the percentage can vary
widely from person to person (Table 1). They are called "natural killers" because
of their innate abilities, i.e., they, they can kill a wide range of abnormal
(malignant or virally-infected) cells without having had any previous exposure
to the abnormal cell and/or its antigens. They usually kill by making cell-to-cell
contact with a target cell, then creating pores in the membrane of the target
cell through which toxic granules are delivered, causing the lysis and/or death
of the target cell. Like other cells of the innate immune system, NK cells are
not able to recognize specific antigens on the surface of cells with which they
interact. It was, therefore, a puzzle to immunologists for many years as to
how NK cells could discriminate between abnormal cells that should be killed
and normal cells that should be left alone. It is now known that NK cells make
the decision to kill or not to kill by using two types of cell surface receptors.
One type of receptor recognizes self MHC molecules on the potential target cell,
and delivers an inhibitory or "don't kill" signal to the NK cell. It is known
that a second type of receptor delivers an activating or "kill" signal to the
NK cell, but it is still not clear exactly what the activating receptors recognize
on the target cell. If a cell is normal, expressing proper levels of the MHC
molecules, the inhibitory signal overrides the activating signal, preventing
the NK cell from killing that cell. In contrast, abnormal cells like malignant
tumor cells and virally-infected cells often have greatly-reduced expression
of MHC molecules. In this case, there is no inhibitory signal given to the NK
cell and it acts in response to the activating signal received, killing the
abnormal cell.
NK cells are a very important component of the innate immune system,
providing a first line of defense against virally-infected cells in much the
same way that phagocytic neutrophils serve as the first line of defense against
extracellular pathogens. NK cells may also play a role in protecting the body
from cancerous cells. Because they are innate rather than antigen-specific,
NK cells do not have immunologic memory, i.e., are not able to remember and
kill the same type of infected cell more efficiently on a second or subsequent
encounter. However, because they are pre-existing circulating cells with a straightforward
recognition and response mechanism, NK cells respond quickly, effectively eliminating
at least some viral infections without any need for an antigen-specific response.
If NK cells are unable to eliminate a viral infection, they play a vital role
in keeping it under control for several days until the adaptive immune system
has been activated to respond. Similar to monocytes and macrophages, activated
NK cells also contribute to the enhancement of both innate and adaptive immune
responses by other cells types through the secretion of cytokines.
The remaining lymphocytes consist of two subsets, B and T lymphocytes,
as shown at the top of Figure 1. It is only these two kinds of lymphocytes that
have the capacity to recognize individual antigens and mount adaptive or antigen-specific
responses. Therefore, the ability of the immune system to respond in an antigen-specific
fashion rests completely with the B and T lymphocytes. For the purposes of further
discussion, all future mention of lymphocytes refers just to B and/or T lymphocytes,
not to the non-specific NK cells.
B and T lymphocytes, more commonly referred to as B and T cells, appear identical
when examined under a microscope. For decades, identification and/or separation
of B and T cells required techniques that relied on the different functions
of the subsets. Since the introduction of monoclonal antibodies as reagents
for identifying proteinsidentifying proteins expressed on the surface of cells,
B and T cells subsets are easily identified by characteristic cell-surface markers.
(A more detailed discussion of monoclonal antibodies and cell surface markers
follows below.). However, it is essential to understand the different functions
that these lymphocyte subsets perform.
B cells account for approximately 5-20%
of the circulating lymphocytes in the blood (Table I), and so represent a small
minority of the total circulating WBCs. They were originally called B cells
because they were first described in chickens, where "B cells" mature in an
organ found near the rectum in birds called the bursa of Fabricius. Mammals
do not have a bursa of Fabricius, but fortunately for the sake of nomenclature,
"B cells" in mammals are both produced by and mature in the bone marrow.
B cells
are antigen-specific cells, capable of binding and responding to individual
antigens, because they carry antigen receptor molecules on their cell surfaces.
Just as each antigen has a distinctive, three-dimensional shape, antigen receptor
molecules have a three-dimensional antigen-binding pocket which is complementary
to the antigen that it binds. The exquisitely specific interaction of an antigen
with its specific receptor is like a key fitting into a lock, and only the proper
specific antigen receptor can bind to a particular antigen.
Each individual
B cell carries thousands of identical antigen receptor molecules on its surface.
This means that any one B cell can recognize only a single antigen, which gives
the immune system great specificity. At the same time, each circulating B cell
has a different antigen receptor, each with a different specificity, which also
gives the immune system incredible diversity. It is estimated that the combination
of specificity and diversity by the immune system provides more than one hundred
million different antigen-specific cells, enough to recognize every antigen
a person is likely to encounter in his or her lifetime (1).
The molecule that serves as the antigen receptor on the surface of B cells is a membrane-bound
form of immunoglobulin (also known as antibody). This is the same protein molecule
that is secreted by B cells when they become antibody-producing plasma cells.
Mature but resting B cells, that have not yet encountered the antigen
for which they are specific, make immunoglobulin molecules, but they are not
secreted from the cell. Instead, these molecules remain attached to the surface
of the cell, where they serve as the B cell receptor for antigen (also known
as the BCR). If and when a B cell encounters the antigen to which its surface
immunoglobulin molecules can bind, the binding of antigen will initiate a complex
sequence of events that can convertcan convert the resting B cell into an antibody-secreting
plasma cell. This process is described and discussed in the following course
of this immunology overview (3).
B cells are designed to recognize and respond
to soluble, extracellular antigens that have not yet been phagocytosed and processed
by an APC. If an antigen is circulating in the blood, it will likely be trapped
by the spleen, where contact with a B cell would occur. Likewise, if a soluble
antigen is introduced into the body via the tissues (which is how most antigen
enters), and is not eliminated by the innate immune response, it will most likely
be filtered out by the lymph system, and will stimulate a B cell response in
a draining lymph node. The cell surface immunoglobulin, which is a Y-shaped
molecule, is anchored in the B cell surface by the base of the Y, with the arms
of the Y extending out into the blood or lymph. The antigen-binding pockets
are located on the very tips of the arms, where they are most likely to encounter
soluble antigens. When the proper antigen binds to the antigen-binding pockets
on the arms of two adjacent immunoglobulin molecules (a necessary step known
as crosslinking), a signal is transmitted to the nucleus of the B cell, which
begins the process of activation. If the activation process is successful, immunoglobulin
with the same antigen specificity as the antigen receptor is actively secreted
by the newly-developed plasma cell out into the blood and the lymph. This specific
immunoglobulin can then bind to and eliminate the soluble antigen that initiated
the response.
T lymphocytes, or T cells, make up the bulk of the circulating
lymphocytes, accounting for approximately 60-85% of the lymphocytes in the blood
(Table I). They are called T cells because immature T cell precursors, which
are produced in the bone marrow, go to the thymus to become fully mature "T
cells.". The thymus, a flat bilobed organ located above the heart, is the anatomic
location where T cells "learn" what is self MHC, and what are self and foreign
antigens. (B cells go through an analogous process while maturing in the bone
marrow.) The thymus is very large in newborn infants, covering the heart, and
may have to be partially removed if cardiac surgery is required. With age, the
thymus atrophies, leaving only a small amount of tissue by adulthood. This residual
thymus may still serve to "educate" newly-produced T cell precursors.
As with
B cells, T cells are antigen-specific cells which carry receptors on their cell
surfaces that bind antigen with great specificity. Just as with B cells, all
of the thousands of antigen receptors on a single T cell are identical, capable
of binding a single antigen, and each T cell differs in its antigen specificity.
However, unlike B cells, the antigen receptor on T cells is not cell surface
immunoglobulin, and can only recognize cell-associated, not soluble, antigens.
The antigen receptor for T cells, which was discovered many years after the
cell surface immunoglobulin receptor on B cells, is rather unimaginatively called
the T cell receptor, or TCR. It is similar in structure to immunoglobulin, with
one end anchored in the cell membrane, and the other, which contains the antigen-binding
pocket, extending out into the surrounding medium. It differs significantly
from cell surface immunoglobulin, however, in the form of antigen that it can
recognize. In contrast to B cells, T cells are designed to recognize and respond
only to processed, cell-associated antigens. The binding pocket of the TCR binds
to a combination of a digested fragment of an antigen plus a self MHC molecule,
as it would be presented on the surface of an APC (as described above) or present
on an infected or defective cell. The TCR, therefore, cannot recognize antigen
that is still in an intact or native form, and can only successfully recognize
antigen (and transmit an activation signal to the nucleus of the T cell) if
both foreign antigen and self MHC are properly presented to it.
As shown in
Figure 1, there is a further subdivision of T cells into two T cell subsets,
known as CD4+ and CD8+ T cells. CD4 and CD8 refer to two cell surface molecules
that are mutually exclusive in their expression on mature T cells. T cells
express either the CD4 molecule (CD4+), or the CD8 molecule (CD8+), but not
both (under normal circumstances). These two subsets, while both using TCR as
their antigen receptor, also use either the CD4 or CD8 molecule when interacting
with processed antigen plus MHC. This gives rise to an important difference
in MHC recognition: CD4+ T cells recognize antigen plus one type of MHC molecule,
Class II MHC, while CD8+ T cells recognize antigen plus MHC Class I molecules.
These differences in CD4 and CD8 expression, and the resulting difference in
MHC recognition, are manifested in two distinctly different functions in the
two T cell subsets.
The CD4+ T cells are known as T helper cells (TH), which,
as suggested by their name, provide help to the other antigen-specific lymphocytes
(B cells and CD8+ T cells). They recognize processed antigen presented by antigen-presenting
cells in association with Class II MHC. Under normal circumstances, only certain
immune system cells, e.g., monocytes/macrophages, dendritic cells, and B cells,
are allowed to express MHC Class II molecules. This ensures that TH recognize
antigen and become fully activated, only when they are in contact with the proper
cells of the immune system that are intended to serve as antigen-presenting
cells. TH provide help primarily through the secretion of cytokines, which deliver
critical signals necessary for the activation and development of B cells into
plasma cells, and CD8+ T cells into cytotoxic T lymphocytes (CTL). These cellular
interactions are presented in the following course of this immunology overview
(3). As shown in Table I, there are usually more CD4+ T cells than CD8+ T cells.
This may be expressed as a CD4:CD8 ratio, which in a healthy individual is typically
about 2:1.
CD8+ T cells, also known as T killer cells or cytotoxic T lymphocytes
(CTL), are capable of killing other cells that are displaying foreign antigen
on their surfaces. The manner in which the target cell is killed is identical
to that used by NK cells, i.e., by making cell-to-cell contact, creating pores
in the membrane of the target cell, delivering toxic granules, and causing its
lysis and death. However, unlike the innate NK cells, T cytotoxic cells use
their TCR to recognize and kill in an antigen-specific fashion.
CD8+ T cells
recognize and kill cells that are displaying foreign antigen plus self-MHC Class
I. When cells are infected with cell-associated pathogens (such as viruses,
intracellular bacteria, or parasites), fragments of foreign proteins belonging
to those pathogens become associated with MHC Class I molecules within the cell.
These antigen fragment/MHC I complexes are then transported to and appear on
the infected cell's surface. In contrast to MHC Class II molecules on APCs,
MHC Class I molecules are not restricted in their expression, and appear on
virtually every nucleated cell in the body. This enables CD8+ CTL to eliminate
any cell in the body that is either infected, or sufficiently defective so as
to appear to be foreign.
Since the 1970s, there has been some evidence that
there were T cells capable of suppressing B cell antibody responses and/or T
cell cytotoxic responses. However, a distinct subpopulation capable of suppression
could not be identified, and the idea of "suppressor T cells" fell out of favor.
However, over the last few years, new cellular and molecular biology techniques
have demonstrated a small naturally-occuringoccurring subpopulation of CD4+
T cells that can suppress other activated T cells in an antigen-specific manner
(1). These cells, now referred to as T regulatory cells (Tregs), require cell-to-cell
contact to exert their effects, and may play an important role in down-regulating
immune responses. If that is indeed true, it raises a host of intriguing possibilities.
For example, it might be possible that the activity of Tregs could be increased
in an effort to control allergic or autoimmune diseases, where the immune system
is overactive, and/or to suppress transplant rejection. Conversely, reducing
Tregs activity (i.e., alleviating suppression) might improve desirable immune
responses to immunizations and/or tumors. The origin and function of Tregs are
still poorly defined, but are likely to continue to be the subject of intense
immunologic research in the years to come.
II. Essential cell surface molecules
All cells have many different molecules on their surfaces. Some of these molecules
are shared among several cell types, both within and outside of the immune system,
while other molecules are unique to a particular WBC type and/or appear only
during certain stages of maturation or activation. The biological function is
known for many well-characterized cell surface molecules, but remains a mystery
for others, that serve purely as markers of certain cell types (1,4,5,
4, and 5). It is important to review a number of cell surface molecules that
are important to the immune system, either as markers used to distinguish between
WBC types or which play critical roles in the generation of immune responses.
Monoclonal antibodies and the CD nomenclature
The routine use of cell surface
molecules as identifiers of different cell types, stages and/or function has
come about as a result of the development of monoclonal antibodies. A monoclonal
antibody is a pure preparation of antibody molecules, in which every antibody
molecule is identical, so that every antibody in the preparation recognizes
and binds to the same known antigen (1). They are powerful antigen-specific
reagents, which indicate by their binding (or lack of binding) that the antigen
in question is present (or absent) on the surface of cells being analyzed. Monoclonal
antibodies are made by fusing a normal antibody-secreting plasma cell (that
which has a limited life span) with a malignant myeloma cell - a , a cancerous
B cell that can grow indefinitely. The resulting cell, known as a B cell hybridoma,
produces antibodiesproduces antibodies with the same, single antigen specificity
as the original normal plasma cell, but can now do so indefinitely. The B cell
hybridoma becomes a perpetual source of an absolutely pure preparation of antibodies
with a single specificity. Once the monoclonal antibodies produced by a hybridoma
have been characterized to identify the antigen recognized, they can be used
to determine the presence or absence of that antigen on cells.
As monoclonal
antibodies came into widespread use, there arose considerable confusion arose
over precisely what each antibody preparation was recognizing. Different monoclonal
antibodies, produced by different laboratories and/or companies and each with
a different name, appeared to recognize the same cell surface antigen. As is
so often the case when there is confusion over nomenclature, an international
committee was formed to address the rapidly proliferating number and names of
monoclonal antibodies. The committee, in laboratories all over the world, tested
all the known, widely used monoclonal antibodies available at the time against
one another, and established a standardized nomenclature for the antigens that
they recognized (4,5). This culminated in 1982, with the first International
Workshop on Human Leukocyte Differentiation Antigens (HLDA), where the term
"cluster of differentiation,", or " "CD"" was introduced.
A cluster of differentiation
(CD) refers to a group of monoclonal antibody preparations that react with a
particular molecule. Therefore, the focus of the nomenclature is on the antigen
that is recognized by one or more monoclonal antibodies, rather than the name
of the individual monoclonal antibody preparation(s). The CD number of the antigen
is used to identify any monoclonal antibody preparation that recognizes that
antigen. For example, as described above, CTLs express the CD8 antigen, and
all the monoclonal antibodies that are known to recognize that CD8 antigen are
simply referred to as "CD8 antibodies.". Any T cell to which a CD8 antibody
binds would be considered "CD8-positive" (CD8+).
As the term HLDA implies, the
CD nomenclature was initially applied only to leukocyte antigens, and only to
those antigens that were detectable on the cell surface. Over the years, however,
CD designations have been expanded to include both cell surface and intracellular
molecules on a wide range of cell and tissue types. As of the 8th HLDA8th HLDA
Workshop, held in December 2004, CD designations have been assigned up to CD339
(1,4, 4). In addition, the name of molecules described by the CD nomenclature
has been changed from Human Leukocyte Differentiation Antigens to Human Cell
Differentiation Molecules (HCDM). The most current list of CD designations is
available online, and provides extensive links to genetic and research data
on CD and related molecules (4). For more general descriptive information about
CD molecules up to CD234, another helpful resource is an earlier website (5),
but it has not been updated since 2001 and so some material may be dated.
Cell
surface molecules that define different types of WBCs
Most analyses of WBCs
from the blood are performed utilizing monoclonal antibodies tagged with fluorescent
labels and a sophisticated laser-based cell counting instrument called a flow
cytometer (a topic that is covered in more detail in the following course
in this series).). Each cell that passes through the flow cytometer is counted,
and evaluated for the presence or absence of labeled monoclonal antibodies,
which indicates the presence or absence of the CD antigen recognized by the
antibodies. The flow cytometry analysis provides the percentage of cells that are positive for each CD antigen examined, which can then be used to calculate
absolute cell numbers (number of cells/microliter of blood) of different cell
types. Not all clinical laboratories are equipped with a flow cytometer, so
not every clinical Clinical laboratory Laboratory Sscientist may have a role
in performing or reporting the results of subset determinations. However, it
may be helpful to be familiar with the CD designations that define different
types of WBCs.
The most common flow cytometric analysis in a clinical setting
is a determination of the three lymphocyte subsets-B cells, T helper cells,
and T cytotoxic cells. The CD antigens utilized for identification of these
subsets, and an example of reference ranges for values obtained from peripheral
blood, are shown in Table I.
B cells express several different CD antigens that
can be used to distinguish between B cells and other types of WBCs (4, 5).
However, the expression of some of these antigens changes with the developmental
stage and/or anatomic location of B cells. As shown in Table I, B cells in the
peripheral blood can be identified by the cell surface molecule CD19, which
is expressed on all B cells (except fully mature plasma cells), and is not expressed
on any other type of peripheral blood WBCs (4,5). Other laboratories may use
CD20, 21, and/or 22 for B cell determinations, depending on the patient population
and clinical situations being evaluated.
All T cells, and only T cells, express
the CD3 antigen. Since there are two subsets of T cells that can be distinguished
by the expression of either CD4 or CD8 (as described above), T cells are usually
evaluated with a combination of CD3 plus either CD4 or CD8. TH and CTL subset
analyses are performed by determining the percentage of all lymphocytes that
express CD3 and CD4 (TH) or CD3 and CD8 (CTL). This double expression is important
to clearly identify T cell subsets, as CD4 and CD8 antigens are also expressed
on other cell types besides T cells (4, 5).
NK cells, which cannot be distinguished
from other lymphocytes on the basis of morphology, can also be included as part
of lymphocyte subset analyses (Table I). They can be identified by the expression
of CD16 and/or CD56, which are not found on other types of lymphocytes. However,
CD16 is also expressed on neutrophils, so NK analyses using CD16/CD56 must be
restricted to lymphocytic (non-granular) cells, as described in a footnote in
Table I. Other types of peripheral blood WBCs can also be characterized utilizing
CD antigens, but such an analysis is rarely done, since monocytes and the three
types of granulocytes can be distinguished by morphology alone. However, for
the record, monocytes can be identified by the strong expression of CD14, and
neutrophils can be identified by CD16 expression in granular cells (4, 5).
Other cell surface molecules critical to immune responses
There are many additional
molecules present on the surface of WBCs besides those used to identify WBC
subsets that are important to immune system function. As described above, Class
I and Class II MHC molecules on the surface of cells participate in T cell/APC
interactions, and are required for the recognition of self vs. non-self (including
transplant rejection) by the immune system. Likewise, cell surface immunoglobulin
on B cells and TCR on T cells act as antigen-specific receptors. While the importance
of secreted cytokines in innate and adaptive immune responses was described
above, it has not yet been mentioned that cytokines can only act on cells that
express cell surface receptors designed to receive the signal from that particular
cytokine (2). Hence, the presence or absence of cytokine receptors on a cell's
surface will dictate its ability to participate in immune responses, and a large
number of CD designations are now dedicated to these receptors. A variety of
other cell surface molecules serve to facilitate cell-to-cell contacts (adhesion
molecules), enhance T and/or B cell activation (co-stimulatory molecules), and
regulate cellular proliferation and/or differentiation, but further discussion
of these is beyond the scope of this course.
III. Beyond the WBCs
This course
provides an initial insight into the workings of the immune system, by reviewing
the first line of defense, the innate immune system, and the cells which contribute
to both innate and adaptive immune responses. It lays the groundwork needed
to describe how the different types of WBCs must interact with each other to
recognize and respond to foreign antigen present in the body, in order to generate
the more sophisticated adaptive immune response. The information presented here
also provides the basis for a discussion of clinical laboratory measurements
of immune system function. Both of these topics are presented in a second course
that continues this "Overview of the Immune System" (3). For those interested
in further immunologic adventures, two additional courses are available from
CAMLT that focus on the immunology and virology of HIV infection and AIDS.
References
- Kindt, T.J., Goldsby, R.A., Osborne, B.A. Kuby Immunology, 6th Ed. W.H. Freeman and Company, New York. 2006.
- Breen, E.C. Cytokines: The 'Great Communicators'. Advance Newsmagazine for Laboratory Professionals 12:8-12. 2000.
- Breen, E.C. An Overview of the Immune System, Part 2: The Generation and Evaluation of Immune Responses (3.0 CEU). California Association for Medical Laboratory Technology.
- Human Cell Differentiation Molecules, http://www.hlda8.org/HLDAtoHCDM.htm
- Protein Reviews on the Web, http://mpr.nci.nih.gov/prow
Reference Ranges a |
|||
| Total WBC count % Lymphocytes Lymphocyte count |
3.5 – 9.5 x 103 cells/µL 20 – 48 % 1078 – 2828 cells/µL |
||
Lymphocyte Subset |
CD(s) |
% Positiveb Lymphocytes |
Number Positivec Lymphocytes/µL |
| B cells | CD19 | 5 - 22 | 74 - 447 |
| Total T cells | CD3 | 58 - 87 | 767 - 2318 |
| T helper cells | CD3, CD4 | 32 - 59 | 467 - 1350 |
| T cytotoxic cells | CD3, CD8 | 13 - 38 | 201 - 868 |
| NK cells | CD16, CD56 | 3 - 26 | 51 -543 |
a: Reference ranges (5th - 95th percentile) provided as an example (courtesy of Anthony Butch, Ph.D., Clinical Immunology Research Laboratory, UCLA Medical Center)--) - every laboratory should establish its own reference ranges
b: Percentage of each lymphocyte subset is calculated using three-color flow cytometric analysis based on the selection of CD45+ non-granular cells and the expression of the indicated CD antigen
c: Lymphocyte subset count calculated using total lymphocyte count and percent positive lymphocytes value determined by subset analysis
Review Questions Course #: DL-978 - Select
the one best answer for each question
- The majority of the components of
the innate immune system are:
a) antigen-specific
b) immature cells awaiting activating signals
c) ready to act prior to exposure to antigens
d) part of the major histocompatibility complex
- Innate immunity utilizes all of the following as barriers
except:
a) complement
b) skin
c) lysozyme
d) surface immunoglobulin
- The Toll-like receptors can recognize all of the following
except:
a) gram-negative bacterial cell walls
b) single-stranded viral RNA
c) flagellin
d) mammalian DNA
- Granulocytes, monocytes, and lymphocytes:
a) require flow cytometry analyses to identify them
b) are identical to one another in function
c) play a role only in innate immune responses
d) can be differentiated on the basis of morphology
- The first WBC that an extracellular pathogen encounters
upon entering the body is most likely to be a:
a) NK cell
b) neutrophil
c) lymphocyte
d) monocyte
- The innate cell that is an important first line of defense
against virally-infected cells is a:
a) NK cell
b) neutrophil
c) dendritic cell
d) CTL
- All but which of the following is true for monocytes and
macrophages?
a) are antigen-presenting cells
b) are cytokine-secreting cells
c) are restricted to peripheral blood
d) serve as a bridge between innate and adaptive immune responses
- Monocytes and neutrophils are both capable of:
a) antigen presentation
b) phagocytosis
c) cell killing
d) immunoglobulin production
- T lymphocytes are called “T cells” because
they:
a) produce cytokines that regulate body temperature
b) mature in the thymus
c) transit through the thyroid
d) are produced from thymic stem cells
- MHC Class II molecules are normally only allowed to be
expressed on the surface of:
a) monocytes/macrophages, dendritic cells, and B cells
b) NK cells and CTLs
c) TH and Treg cells
d) B and T cells
- A plasma cell is:
a) a fully mature B cell that has responded to antigen
b) an activated dendritic cell
c) capable of killing target cells
d) attracted by chemokines to a site of inflammation
- The ability to recognize and respond to specific antigens
is found in:
a) T cells only
b) B cells, T cells, and NK cells
c) B and T cells
d) basophils
- Basophils participate in:
a) B cell development
b) transplant rejection
c) CTL responses
d) allergic responses
- Eosinophils have been observed to be elevated in association
with:
a) viral infections
b) bacterial sepsis
c) parasitic infections
d) autoimmune disease
- NK cells will kill a potential target cell when:
a) low levels of MHC molecules on the target cell fail to deliver an inhibitory signal
b) low levels of MHC molecules on the target cell deliver a “kill” signal
c) over expression of MHC molecules on the target cell activates the NK cell
d) antigen receptors recognize foreign antigen plus self MHC on the target cell
- NK cells and CTLs:
a) both kill by making cell-to-cell contact, then delivering toxic granules
b) both utilize a TCR to recognize antigen
c) both require cell-to-cell contact with an antigen-presenting dendritic cell
d) differ in their killing mechanism due to cytokine secretion by CTLs
- B cells bind and respond to antigen that:
a) is soluble, especially in the spleen and lymph nodes
b) is presented with MHC molecules on the surface of an APC
c) is restricted to the cytoplasm of a cell
d) is phagocytosed and digested by a neutrophil
- T cells recognize and respond to antigen that:
a) is presented with MHC molecules on the surface of an APC
b) is soluble, especially in the spleen and lymph nodes
c) is restricted to the cytoplasm of a cell
d) is phagocytosed and digested by a neutrophil
- The cell surface molecule used as a specific receptor for
antigen on T cells is:
a) TLR
b) TCR
c) CD4
d) CD8
- Under normal circumstances, CD4+ T cells recognize and
respond to:
a) foreign antigen plus self MHC Class I molecules
b) foreign antigen plus self MHC Class II molecules
c) self antigens plus any foreign MHC molecules
d) self antigens plus self MHC Class II molecules
- The function of CD4+ T cells is to:
a) initiate innate inflammatory responses
b) contact and kill virally-infected cells
c) monitor the body for potentially cancerous cells
d) provide help to other cells of the immune system
- CD4+ T cells perform their function by:
a) recognizing abnormal levels of MHC molecules
b) creating pores in the membrane of the target cell to be killed
c) secreting cytokines
d) secreting antibody to bind and clear soluble antigens
- CD8+ T cells recognize and respond to:
a) self antigens plus self MHC Class I
b) any cell expressing foreign MHC molecules
c) foreign antigen plus self MHC Class I
d) microbial antigens via TLRs
- Monoclonal antibodies are:
a) characteristic antibodies found in the circulation of persons recovering from acute mononucleosis
b) antigen-specific antibody preparations purified from the blood of individuals with myeloma
c) genetically-engineered clones of naturally-occurring antibodies
d) a pure preparation of identical antibody molecules secreted by a hybridoma
- “HCDM ” describes:
a) Hybridoma Culture Defined Molecules, a group of cell surface molecules that are recognized by a single monoclonal antibody preparation
b) the Human Cell Differentiation Molecules categorized by the “CD” nomenclature
c) the Human Classification Designations for Mammalian cells
d) the Hybridoma Committee for Defining Monoclonals, the international committee responsible for “CD” designations
- A CD4+ Treg cell in the peripheral blood:
a) will co-express CD4 and CD8 on its surface
b) exerts its regulatory effects via secreted molecules
c) will express CD3 on its surface
d) can suppress NK cell killing
- B cells can be distinguished from other cells by their
expression of:
a) CD339
b) CD56
c) CD14
d) CD19
- A CD3+, CD8+ cell is:
a) an innate cytotoxic cell
b) capable of antigen-specific cell lysis
c) capable of phagocytosis
d) an immature cell found in the thymus
- Among the lymphocytes in the peripheral blood, the most
plentiful cell type is usually:
a) TH cells
b) CTLs
c) NK cells
d) B cells
- A cytokine signal sent by one WBC:
a) will stimulate only those cells that are expressing receptors for that particular cytokine
b) can be detected by any other WBC in the vicinity
c) is produced in very large amounts in order to be able to stimulate in a non-specific fashion
d) affects only cells in the immediate area that are expressing TLRs