extracellular environment by macrophages and B lymphocytes enter the class II MHC pathway of antigen
extracellular microbes and toxins.
CHAPTER 3 Antigen Capture and Presentation to Lymphocytes 71
Finally, it should be mentioned that T cells also
recognize and react against small molecules and even
metal ions in an MHC-restricted manner. In fact,
exposure to some small molecules that are used as
therapeutic drugs and to metals such as nickel and
beryllium often leads to pathologic T cell reactions
(so-called hypersensitivity reactions; see Chapter 11).
CD8+ T cells. Some of the chemicals are thought to
covalently modify self peptides or the MHC molecules
peptide-binding cleft such that the MHC molecule can
display peptides that are not normally presented and
these peptide-MHC complexes are seen as being foreign.
This chapter began with two questions: how do rare
antigen-specific lymphocytes find antigens, and how are
the appropriate immune responses generated against
extracellular and intracellular microbes? Understanding
the biology of APCs and the role of MHC molecules in
displaying the peptides of protein antigens has provided
satisfying answers to both questions, specifically for T
cell–mediated immune responses.
FUNCTIONS OF ANTIGEN-PRESENTING
Antigen-presenting cells not only display peptides for
recognition by T cells but, in response to microbes,
also express additional signals for T cell activation.
The two-signal hypothesis of lymphocyte activation was
introduced in Chapters 1 and 2 (see Fig. 2.19), and we will
return to this concept when we discuss the responses of T
and B cells in Chapters 5 and 7. Recall that antigen is the
necessary signal 1, and for T cells, signal 2 is provided by
APCs reacting to microbes. The expression of molecules
microbial products. For example, many bacteria produce
a substance called lipopolysaccharide (LPS, endotoxin).
When the bacteria are captured by APCs for presentation
of their protein antigens, LPS acts on the same APCs,
and cytokines act in concert with antigen recognition by
the T cell to stimulate the proliferation of the T cells and
their differentiation into effector and memory cells.
ANTIGEN RECOGNITION BY B CELLS AND
Chapter 7). The secreted antibodies enter the circulation
and mucosal fluids and bind to the antigens, leading to
recognize antigens in the native conformation, with no
dendritic cells adjacent to follicles may capture antigens
that enter lymph nodes and present the antigens, in intact
(unprocessed) form, to B lymphocytes in the follicles.
The B cell–rich lymphoid follicles of the lymph nodes
antigens to activated B cells. FDCs are not bone-marrow
derived or related to the dendritic cells that process and
present antigens to T cells. FDCs express receptors that
bind antigens coated with antibodies or complement
by-products such as C3b and C3d, with no role for MHC
and they function to select B cells that bind the antigens
with high affinity. This process is discussed in Chapter 7.
are other, smaller populations of T cells that recognize
different types of antigens. Natural killer T cells (called
NK-T cells), which are distinct from the natural killer
(NK) cells described in Chapter 2, are specific for lipids
MR1 molecules. ?d T cells recognize a wide variety of
molecules, some displayed by class I–like molecules and
their unusual specificities are poorly understood.
72 CHAPTER 3 Antigen Capture and Presentation to Lymphocytes
• The induction of immune responses to the protein
antigens of microbes depends on a specialized system for capturing and displaying these antigens for
recognition by the rare naive T cells specific for any
antigen. Microbes and microbial antigens that enter
regional lymph nodes or captured by dendritic cells
in lymph nodes and spleen. The protein antigens of
the microbes are displayed by the antigen-presenting
cells (APCs) to naive T lymphocytes that recirculate
• Molecules encoded in the major histocompatibility
complex (MHC) perform the function of displaying
peptides derived from protein antigens.
• MHC genes are highly polymorphic. Their major
products are class I and class II MHC molecules,
which contain peptide-binding clefts, where the
polymorphic residues are concentrated, and invariant regions, which bind the coreceptors CD8 and
• Proteins that are produced in the cytosol of infected
and tumor cells, or that enter the cytosol from phagosomes, are degraded by proteasomes, transported
into the endoplasmic reticulum by TAP and bind to
the clefts of newly synthesized class I MHC molecules. CD8 binds the invariant part of class I MHC
molecules, so CD8+ cytotoxic T lymphocytes can be
activated only by class I MHC–associated peptides
derived from proteosomal degradation of cytosolic
• Proteins that are ingested by APCs from the extracellular environment are proteolytically degraded
MHC molecules. CD4 binds to class II MHC, because
of which CD4+ helper T cells can only be activated
by class II MHC–associated peptides derived mainly
from proteins degraded in vesicles, which are typically ingested extracellular proteins.
• The role of MHC molecules in antigen display
ensures that T cells only recognize cell-associated
protein antigens and that the correct type of T cell
(helper or cytotoxic) responds to the type of microbe
the T cell is best able to combat.
• Microbes activate APCs to express membrane proteins
(costimulators) and to secrete cytokines that provide
Follicular dendritic cells display antigens to germinal
center B cells and select high-affinity B cells during
1. When antigens enter through the skin, in what
organs are they concentrated? What cell type(s) plays
an important role in this process of antigen capture?
2. What are MHC molecules? What are human MHC
molecules called? How were MHC molecules discovered, and what is their function?
3. What are the differences between the antigens that
are displayed by class I and class II MHC molecules?
4. Describe the sequence of events by which class I and
class II MHC molecules acquire antigens for display.
5. Which subsets of T cells recognize antigens presented by class I and class II MHC molecules? What
molecules on T cells contribute to their specificity
for either class I or class II MHC–associated peptide
Answers to and discussion of the Review Questions are
Structure of Lymphocyte Antigen
Antigen receptors serve critical roles in the maturation
of lymphocytes from progenitors and in all adaptive
effector T cells and antibodies recognize antigens to
B and T lymphocytes express different receptors that recognize antigens: membrane-bound
antibodies on B cells and T cell receptors (TCRs)
responses of the cells on which the receptors are
expressed. To recognize a large variety of different
antigens, the antigen receptors of lymphocytes must
be able to bind to and distinguish between many,
often closely related, chemical structures. Antigen
receptors are clonally distributed, meaning that each
lymphocyte clone is specific for a distinct antigen and
has a unique receptor, different from the receptors of
clone of B lymphocytes or T lymphocytes recognizes
a different antigen, the antigen receptors transmit
biochemical signals that are fundamentally the same
in all lymphocytes and are unrelated to specificity.
Antigen Receptors of Lymphocytes, 74
Binding of Antigens to Antibodies, 78
T Cell Receptors for Antigens, 80
Antigen Recognition by the T Cell Receptor, 80
Development of B and T Lymphocytes, 83
Production of Diverse Antigen Receptors, 86
Inherited Antigen Receptor Genes, 86
Somatic Recombination and Expression of Antigen
Mechanisms of V(D)J Recombination, 88
Generation of Ig and TCR Diversity, 89
Maturation and Selection of B Lymphocytes, 89
Early Steps in B Cell Maturation, 89
Role of the Pre-BCR Complex in B Cell Maturation, 91
Completion of B Cell Maturation, 92
Selection of Mature B Cells, 92
Maturation and Selection of T Lymphocytes, 92
Early Steps in T Cell Maturation, 93
Selection of Mature T Cells, 94
74 CHAPTER 4 Antigen Recognition in the Adaptive Immune System
These features of lymphocyte recognition and antigen
receptors raise the following questions:
• How is the vast diversity of receptor structures in
the lymphocyte repertoire generated? The diversity
of antigen recognition implies the existence of many
structurally different antigen receptor proteins, more
than can be encoded in the inherited genome (germline). Therefore, special mechanisms must exist for
receptors recognize antigens. We also discuss how the
diversity of antigen receptors is generated during the
process of lymphocyte development, thus giving rise to
the repertoire of mature lymphocytes. The process of
antigen-induced lymphocyte activation is described in
ANTIGEN RECEPTORS OF LYMPHOCYTES
adaptive immunity (Fig. 4.1). Although these receptors
related to the types of antigenic structures that B cells
• Membrane-bound antibodies, which serve as the
antigen receptors of B lymphocytes, can recognize
histocompatibility complex (MHC) molecules. B
lymphocyte antigen receptors and the antibodies that
carbohydrates, and nucleic acids, as well as simpler,
smaller chemical moieties. This broad specificity of
B cells for structurally different types of molecules in
their native form enables the humoral immune system to recognize, respond to, and eliminate diverse
microbes and toxins. In striking contrast, T cells see
only peptides displayed on antigen-presenting cells
(APCs) bound to MHC molecules. This specificity
ensures that T cells never interact with free or soluble
antigens and that they only interact with microbial or
tumor antigens present inside other cells in the body.
• Antigen receptor molecules consist of regions
(domains) involved in antigen recognition—
therefore varying between clones of lymphocytes—
and other regions required for structural integrity
and effector functions—thus relatively conserved
among all clones. The antigen-recognizing domains
of the receptors are called variable (V) regions, and
the conserved portions are the constant (C) regions.
are called hypervariable regions, or complementarity-determining regions (CDRs), because they form
the parts of the receptor that bind antigens (i.e., they
are complementary to the shapes of antigens). By
concentrating sequence variation in small regions of
the receptor, it is possible to maximize the variability
of the antigen-binding part while retaining the basic
structure of the receptors. As discussed later, special
mechanisms exist in developing lymphocytes to create genes that encode different variable regions of
antigen receptor proteins in individual clones.
intracellular signals following antigen recognition
(see Fig. 4.1). These signals, which are transmitted to
the cytosol and the nucleus, may cause a lymphocyte
two functions of lymphocyte receptors for antigen—
specific antigen recognition and signal transduction—
are mediated by different polypeptides. This again
allows variability to be segregated in one set of molecules—the antigen receptors themselves—while
membrane antigen receptor and signaling molecules
in B lymphocytes is called the B cell receptor (BCR)
complex, and in T lymphocytes it is called the T cell
receptor (TCR) complex. When antigens bind to
the extracellular portions of the antigen receptors of
lymphocytes, intracellular portions of the associated
signaling proteins are phosphorylated on conserved
tyrosine residues by enzymes called protein tyrosine
kinases. Phosphorylation triggers complex signaling cascades that culminate in the transcriptional
Antigen-presenting cell Membrane Ig
specificity; potential* for ~1011
number of possible receptors with unique binding sites is very large, but only ~107–109
76 CHAPTER 4 Antigen Recognition in the Adaptive Immune System
activation of many genes and the production of
numerous proteins that mediate the responses of the
lymphocytes. We return to the processes of T and B
lymphocyte activation in Chapters 5 and 7, respectively.
• Antibodies exist in two forms—as membrane-bound
antigen receptors on B cells and as secreted proteins—but TCRs exist only as membrane receptors on
T cells. Secreted antibodies are present in the blood
are also called immunoglobulins (Igs), referring to
immunity-conferring proteins with the physical
domains, the same as the membrane-bound antigen
receptors of B lymphocytes. The constant regions of
some secreted antibodies have the ability to bind to
other molecules that participate in the elimination of
antibodies serve different functions at different stages
of humoral immune responses: membrane-bound
antibodies on B cells recognize antigens to initiate B
cell activation, and secreted antibodies neutralize and
eliminate microbes and their toxins in the effector
performed by T lymphocytes themselves and by other
leukocytes responding to the T cells. The antigen
not secreted and do not mediate effector functions.
An antibody molecule is composed of four polypeptide chains—two identical heavy (H) chains and two
identical light (L) chains—with each chain containing
a variable region and a constant region (Fig. 4.2). The
four chains are assembled to form a Y-shaped molecule.
Each light chain is attached to one heavy chain, and the
C domain, and a heavy chain has one V and three or
four C domains. Each domain folds into a characteristic
three-dimensional shape, called the immunoglobulin
(Ig) domain (see Fig. 4.2D). An Ig domain consists of
connected by short, protruding a-helical loops; in the
V regions of Ig molecules, three of these loops make
up the three CDRs responsible for antigen recognition.
Ig domains without hypervariable loops are present in
many other proteins in the immune system, as well as
outside the immune system, and most of these proteins
to be members of the immunoglobulin superfamily.
The antigen-binding site of an antibody is composed of the V regions of both the heavy chain and
Each variable region of the heavy chain (called VH) or of
the light chain (called VL) contains three hypervariable
regions, or CDRs. Of these three, the greatest variability
is in CDR3, which is located at the junction of the V
and C regions. As may be predicted from this variability,
CDR3 is also the portion of the Ig molecule that contributes most to antigen binding.
Functionally distinct portions of antibody molecules
attached to the V and first C domains of a heavy chain is
required for antigen recognition and is therefore called
crystalline) region; because this fragment is identical in
all antibody molecules of a particular type, it tends to
crystallize in solution. In each Ig molecule, there are two
identical Fab regions that bind antigen attached to one Fc
region that is responsible for most of the biologic activity
and effector functions of the antibodies. (As discussed
later, some types of antibodies exist as multimers of two
or five Ig molecules attached to one another.) Linking
the Fab and Fc regions of most antibody molecules is a
flexible portion called the hinge region. The hinge allows
the two antigen-binding Fab regions of each antibody
molecule to move independent of each other, enabling
them to simultaneously bind antigen epitopes that are
separated from one another by varying distances.
CHAPTER 4 Antigen Recognition in the Adaptive Immune System 77
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