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CELL BIOLOGY OF THE IMMUNE SYSTEM
In the early fetal development, T-cell lymphopoiesis
(T-cell formation) occurs in the thymic cortex.
A. HEMOPOIETIC STEM CELLS differentiate into lymphoid progenitor cells which form
T stem cells within the bone marrow.
B. Under the influence of thymotoxin, T stem cells leave the bone marrow and enter the
thymic cortex where they differentiate into pre-T cells. Pre-T cells begin TCR gene re-
arrangement and express TCR.
C. IMMATURE T CELLS express TCR, CD4, and CD8 and undergo positive or negative
selection under the influence of thymosin, serum thymic factor, and thymopoietin.
1.
Positive selection
is a process whereby CD4
CD8
T cells bind with a certain
affinity to MHC proteins expressed on thymic epitheliocytes such that the CD4
CD8
T cells become “educated”; all other CD4
CD8
T cells undergo apopto-
sis. This means that a mature T cell will respond to antigen only when presented
by an MHC protein that it encountered at this stage in its development. This is
known as MHC restriction of T-cell responses.
2.
Negative selection
is a process whereby CD4
CD8
T cells interact with thymic
dendritic cells at the cortico-medullary junction of the thymus such that CD4
CD8
T cells that recognize “self” antigens undergo apoptosis (or are somehow
inactivated) leaving only CD4
CD8
T cells that recognize only foreign antigens.
D. MATURE T CELLS downregulate CD4 or CD8 to form CD4
helper T cells, CD4
or
CD8
suppressor T cells, or CD8
cytotoxic T cells.
E.
Mature T cells migrate to the paracortex (thymic-dependent zone) of all lymph nodes,
periarterial lymphatic sheath in the spleen, and GALT to await antigen exposure.
F.
EXOGENOUS ANTIGENS (circulating in the bloodstream).
1.
Exogenous antigens are internalized by APCs and then undergo lysosomal degra-
dation in endolysosomes to form antigen peptide fragments.
2.
The antigen peptide fragments become associated with Class II MHC, transported,
and exposed on the cell surface of the APC.
3.
The antigen peptide fragment
MHC Class II on the surface of the APC is recog-
nized by CD4
helper T cells which secrete IL-2 (stimulates proliferation of B and
T cells), IL-4 and IL-5 (activate antibody production by causing B-cell differentia-
tion into plasma cells and promote isotype switching and hypermutation), TNF-
(activates macrophages), and IFN-
(activate macrophages and NK cells).
G. ENDOGENOUS ANTIGENS (virus or bacteria within a cell).
1.
Endogenous antigens undergo proteosomal degradation in proteosomes within the
infected cell to form antigen peptide fragments.
2.
The antigen peptide fragments become associated with Class I MHC, transported,
and exposed on the cell surface of the infected cell.
3.
The antigen peptide fragment
Class I MHC on the surface of the infected cell is
recognized by CD8
cytotoxic T cells, which secrete perforins, cytolysins, lym-
photoxins, and serine esterases which cause membrane porosity and endonucle-
ase-mediated apoptosis of the infected cell.
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84
CHAPTER 12
● Figure 12-9 T-cell lymphopoiesis.
Positive selection
Negative selection
Hemopoietic stem cell
Lymphoid progenitor cell
T stem cell
Thymotaxin
T stem cell
Pre-T cell
Immature T cell
Mature T cells
TcR
TcR
CD4
CD8
TcR
TcR
TcR
CD4
CD4
CD8
CD8
Thymosin
Serum thymic factor
Thymopoietin
Exogenous
antigen
Endogenous
antigen
or
CD4+ helper
T cells
CD4+ or CD8+
suppressor
T cells
Migrate to:
• Paracortex of lymph nodes
• Peri-arterial lymphatic sheath (PALS) of spleen
• Gut-associated lymphoid tissue (GALT) and
await antigen exposure
CD8+ cytotoxic
T cells
Thymic
medulla
Thymic
cortex
Bone
marrow
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CELL BIOLOGY OF THE IMMUNE SYSTEM
Immune Response to Exogenous Protein Antigens (Figure 12-10).
The
immune response to exogenous protein antigens involves three cells: the mature B cell, an APC,
and a CD4
helper T cell resulting in an early response and a late response to an antigen (X).
A. EARLY RESPONSE
1.
Early in the immune response, mature B cells bind antigen using IgM and IgD.
2.
As a consequence of antigen binding, two transmembrane proteins (CD79a and
CD79b) that function as signal transducers cause proliferation and differentiation
of B cells into plasma cells that secrete either IgM or IgD.
B. LATE RESPONSE
1.
Later in the immune response, APCs (macrophages) phagocytose the antigen (X)
where it undergoes lysosomal degradation in endolysosomes to form antigen pep-
tide fragments.
2.
The antigen peptide fragments become associated with the class II MHC and are
transported and exposed on the cell surface of the APC.
● Figure 12-10 Immune response to exogenous protein antigen.
CD4 +
helper T cells
CD4
Late response
Mature B cell
Antigen-presenting cell (APC)
Antigen
Plasma cell
IgM
IgD
Lymph
Blood
Plasma cell
Isotype
switching
IgG
IgE
IgA
Lymph
Blood
Hypermutation
High affinity
IgG
IgE
IgA
Lymph
Blood
Early response
X
X
X
X
X
X
Class II
MHC
IL-2
IL-4
IL-5
Antigen peptide
fragments
Phagocytic
vacuole
Endolysosome
Phagolysosome
Class II
MHC
IgM
IgD
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CHAPTER 12
3.
The antigen peptide fragment
class II MHC on the surface of the APC is recog-
nized by CD4
helper T cells which secrete.
a.
IL-2 which stimulates proliferation of B and T cells
b.
IL-4 and IL-5 which activate antibody production by causing B-cell differenti-
ation into plasma cells and promote isotype switching and hypermutation
c.
TNF-
which activates macrophages
d.
IFN-
which activates macrophages and NK cells
4.
Under the influence of IL-4 and IL-5, mature B cells undergo isotype switching
and hypermutation.
a.
Isotype switching is a gene rearrangement process whereby the
(mu; M) and
(delta; D) constant segments of the heavy chain (C
H
) are spliced out and replaced
with
(gamma; G), (epsilon; E), or (alpha; A) C
H
segments. This allows ma-
ture B cells to differentiate into plasma cells that secrete IgG, IgE, or IgA.
b.
Hypermutation is a mutation process whereby a high rate of mutations occurs
in the variable segments of the heavy chain (V
H
) and light chain (V
or V
).
This allows mature B cells to differentiate into plasma cells that secrete IgG,
IgE, or IgA that will bind antigen with greater and greater affinity.
Immune Response to Endogenous Antigens (Intracellular Virus or
Bacteria; Figure 12-11)
A. This figure shows the immune response to the hepatitis B virus infecting a hepatocyte
of the liver.
B. The viral DNA enters the hepatocyte nucleus and uses the hepatocyte machinery to
produce viral mRNA and viral proteins.
CD8+
cytotoxic T cell
Class I
MHC
Hepatitis B
virus
Membrane porosity
Endonuclease-mediated apoptosis
Perforin
Cytolysin
Lymphotoxin
Serine Esterase
Hepatocyte
● Figure 12-11 Immune response to endogenous antigen.
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CELL BIOLOGY OF THE IMMUNE SYSTEM
C. The viral proteins undergo proteosomal degradation in proteosomes within the hepa-
tocyte to form antigen peptide fragments.
D. The antigen peptide fragments become associated with the Class I MHC and are trans-
ported and exposed on the cell surface of the infected cell.
E.
The antigen peptide fragment
class I MHC on the surface of the infected cell is rec-
ognized by CD8
cytotoxic T cells which secrete perforin, cytolysins, lymphotoxins,
and serine esterases which cause membrane porosity and endonuclease-mediated
apoptosis of the infected hepatocyte.
A. PROPERTIES
1.
Cytokines are small, soluble, secreted proteins that enable immune cells to com-
municate with each other and therefore play an integral role in the initiation, per-
petuation, and downregulation of the immune response.
2.
Cytokine activity demonstrates redundancy and pleiotropy. Cytokine redundancy
means that many different cytokines may elicit the same activity. Cytokine
pleiotropy means that a single cytokine can cause multiple activities.
3.
Cytokines act in an autocrine manner (i.e., they act on cells that secrete them) or
a paracrine manner (i.e., they act on nearby cells).
4.
Cytokines are often produced in a cascade (i.e., one cytokine stimulates its target
cell to produce additional cytokines).
5.
Cytokines may act synergistically (i.e., two or more cytokines acting with one an-
other) or antagonistically (i.e., two or more cytokines acting against one another).
B. CYTOKINE RECEPTORS. Cytokines elicit their activity by binding to high-affinity cell
surface receptors on target cells thereby initiating an intracellular signal transduction
pathway. Cytokine receptors have been grouped into several families which include
the following:
1.
Hematopoietin family of receptors.
This family of receptors is characterized by
four conserved cysteine residues and a conserved Trp-Ser-X-Trp-Ser sequence in
the extracellular domain. These receptors generally have two subunits, an
-
subunit for cytokine binding and a
-subunit for signal transduction. Cytokine
binding promotes dimerization of the
-subunit and -subunit. This family of
receptors binds IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, erythropoietin, and GM-CSF.
2.
IFN family of receptors.
This family of receptors is characterized by four con-
served cysteine residues but does not have a conserved Trp-Ser-X-Trp-Ser sequence
in the extracellular domain. This family of receptors binds IFN-
, IFN-, IFN-.
3.
TNF family of receptors.
This family of receptors is characterized by four extra-
cellular domains. This family of receptor binds TNF-
, TNF-, membrane-bound
CD40, and Fas (which signals a cell to undergo apoptosis).
4.
Seven-pass transmembrane helix family of receptors.
This family of receptors
is characterized by seven transmembrane domains and the interaction with G-
proteins. This family of receptors binds IL-8, MIP-1 (macrophage inflammatory
protein), and MCP-1 (monocyte chemotactic protein) which are chemokines.
C. CHEMOKINES. Chemokines are chemotactic cytokines that promote chemotaxis (mi-
gration) of leukocytes to inflammatory sites. Chemokines are divided into two groups:
1.
Chemokines-
or C-X-C chemokines.
These chemokines have their first two cys-
teine residues separated by one amino acid.
2.
Chemokines-
or C-C chemokines.
These chemokines have two adjacent cys-
teine residues. This family of receptors is characterized by four conserved cysteine
residues and a conserved Trp-Ser-X-Trp-Ser sequence in the extracellular domain.
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