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T helper cells (TH cells) assist other white blood cells in immunologic processes Cytotoxic T cells (TC cells, or CTLs) destroy virally infected cells and tumor cells T lymphocytes consist of functionally distinct populations: helper T cells and cytotoxic (or cytolytic) T lymphocytes (CTLs). In response to antigenic stimulation, helper T cells secrete proteins called cytokines, which are responsible for many of the cellular responses of innate and adaptive immunity and thus function as the "messenger molecules" of the immune system. The cytokines secreted by helper T lymphocytes stimulate the proliferation and differentiation of the T cells themselves and activate other cells, including B cells, macrophages, and other leukocytes. CTLs kill cells that produce foreign antigens, such as cells infected by viruses and other intracellular microbes and responsible for killing tumor cells.
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T cells Abul K. Abbas: Basic Immunologypage (fig3.7,3.9,3.11,
3.16 are not required) and (fig 5.11, 5.18 are not required) T
helper cells (TH cells) assist other white blood cells in
immunologic processes
Cytotoxic T cells (TC cells, or CTLs) destroy virally infected
cells and tumor cells T lymphocytes consist of functionally
distinct populations: helper T cells and cytotoxic (or cytolytic) T
lymphocytes (CTLs). In response to antigenic stimulation, helper T
cells secrete proteins called cytokines, which are responsible for
many of the cellular responses of innate and adaptive immunity and
thus function as the "messenger molecules" of the immune system.
The cytokines secreted by helper T lymphocytes stimulate the
proliferation and differentiation of the T cells themselves and
activate other cells, including B cells, macrophages, and other
leukocytes. CTLs kill cells that produce foreign antigens, such as
cells infected by viruses and other intracellular microbes and
responsible for killing tumor cells. T cells MHCI, presentation of
intracellular pathogens
MHCII, presentation of extracellular pathogens T cell receptor
(TCR) T cell activation Cytotoxic T cells Helper T cells ! ! II
ANTIGEN RECOGNITION BY T-CELLS REQUIRES
PEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS THAT EXPRESS MHC
MOLECULES ! ! T II Cell surface MHC-peptide complex T-cell response
soluble Ag Peptide antigen Native membrane Ag Cell surface peptides
APC T lymphocytes recognize peptide antigens that are bound to and
displayed bymajor histocompatibility complex (MHC) molecules of
antigen-presenting cells. T cell receptor recognizes a complex of
peptide antigen displayed by an MHCmolecule. Major
histocompatibility complex (MHC) molecules are expressed
onantigen-presenting cells and function to display peptides derived
from proteinantigens. The cells that capture microbial antigens and
display them for recognition by Tlymphocytes are called
antigen-presenting cells (APCs). APC APC No T-cell response
Dendritic cells take up antigen in the tissues, migrate to
peripheral lymphoid organs, and present foreign antigens to naive T
cells. Dendritic cells take up antigen in the tissues, migrate to
peripheral lymphoid organs, and present foreign antigens to naive T
cells. In the example illustrated, of a wound in the skin, immature
dendritic cells in the skin, known as Langerhans cells, take up
antigen locally and migrate to a nearby lymph node. There they
settle in the T-cell areas and differentiate into mature dendritic
cells. 5 Interaction of antigen presenting cell and T cell
TCR MHC peptid T lymphocytes recognize peptide antigens that are
bound to and displayed by major histocompatibility complex (MHC)
molecules of antigen-presenting cells. Antigens that are
transported by dendritic cells to lymph nodes are recognized by
naive T lymphocytes that recirculate through these lymph nodes. The
naive T cells are activated to differentiate into effector and
memory cells, which may remain in the lymphoid organs or migrate to
nonlymphoid tissues. At sites of infection, the effector cells are
again activated by antigens and perform their various functions,
such as macrophage activation. APC T cells MHCI, presentation of
intracellular pathogens
MHCII, presentation of extracellular pathogens T cell receptor
(TCR) T cell activation Cytotoxic T cells Helper T cells System
optimalization 1:
How can the immune system monitor the intracellular enviroment? How
can the immune system detect the intracellular pathogens?
PRR Antigen presentation Display intracellular peptides on the
surface of cells Cellular receptors for pathogens and
damage-associated molecules are often called pattern recognition
receptors (PRRs). They are expressed on the plasma membrane or
endosomal membranes of various cell types and also in the cytoplasm
of these cells. These various locations of the receptors ensure
that the immune system can respond to microbes that may be present
outside cells or within different cellular compartments. Major
histocompatibility complex
MHC Major histocompatibility complex cell surface molecules mediate
interactions ofT cells with antigen presenting cells Major
histocompatibility complex (MHC) molecules are expressed on
antigen- presenting cells and function to display peptides derived
from protein antigens. The cells that capture microbial antigens
and display them for recognition by Tlymphocytes are called
antigen-presenting cells (APCs). Expressed by all nucleated
cells
MHCI Expressed by all nucleated cells the expression is regulated
by cytokines or intectious agents. PEPTIDE 1 3 2 2m MHCI molecules
are constitutively expressed on virtually all nucleated cells but
the expression can be increased by cytokines produced during both
innate and adaptive immune responses. All nucleated cells are
susceptible to viral infections and cancer-causing mutations.
Therefore, it is important that the immune system be able to
recognize cytosolic antigens, such as viral antigens and mutated
proteins, in any cell type. CD8+ CTLs are the cell population that
recognize these antigens and eliminate the cells in which the
antigens are produced. STRUCTURE OF CLASS I MHC MOLECULES
A polymorphic chain and and a non-polymorph 2 mikroglobulin 1 s 2
domains are responsible for peptide binding MHCI molecules consist
of two noncovalently linked polypeptide chains, an chain (or heavy
chain) and a 2-microglobulin. Each chain is oriented so that about
three quarters of the complete polypeptide extends into the
extracellular milieu, a short hydrophobic segment spans the cell
membrane, and the carboxyl-terminal residues are located in the
cytoplasm. The 1 and 2 segments of the chain interact to form the
peptide-binding cleft of class I molecules. Its size is large to
bind peptides of 8 to 11 amino acids in a flexible, extended
conformation. The 3 segment of the chain folds into an Ig domain.
This segment contains the binding site for CD8 and at the end of
the 3 segment is a stretch that traverses the lipid bilayer of the
plasma membrane and anchors the MHC molecule. 2-Microglobulin, the
light chain of class I molecules interacts noncovalently with the 3
domain of the chain. Like the 3 segment, 2-microglobulin is
structurally homologous to an Ig domain. Cleft geometry b2-M
a-chain Peptide a-chain b-chain Peptide
Each MHC molecule consists of an extracellular peptide-binding
cleft, or groove, followed by immunoglobulin (Ig)-like domains and
transmembrane and cytoplasmic domains. Class I molecules are
composed of one polypeptide chain encoded in the MHC and a second,
non-MHC-encoded chain, whereas class II molecules are made up of
two MHC-encoded polypeptide chains. Despite this difference, the
overall three-dimensional structures of class I and class II
molecules are similar. The polymorphic amino acid residues of MHC
molecules are located in and adjacent to the peptide-binding cleft.
This cleft is formed by the folding of the MHC-encoded proteins.
The polymorphic residues, which are the amino acids that vary among
different MHC alleles, are located in and around this cleft. This
portion of the MHC molecule binds peptides for display to T cells,
and the antigen receptors of T cells interact with the displayed
peptide and with the helices of the MHC molecules. Because of amino
acid variability in this region, different MHC molecules bind and
display different peptides and are recognized specifically by the
antigen receptors of different T cells. The nonpolymorphic Ig-like
domains of MHC molecules contain binding sites for the T cell
molecules CD4 and CD8. CD4 and CD8 are expressed on distinct
subpopulations of mature T lymphocytes and participate, together
with antigen receptors, in the recognition of antigen; that is, CD4
and CD8 are T cell "coreceptors" . CD4 binds selectively to class
II MHC molecules, and CD8 binds to class I molecules. This is why
CD4+ helper T cells recognize class II MHC molecules displaying
peptides, whereas CD8+ T cells recognize class I MHC molecules with
bound peptides. MHC class I accommodate peptides of 8-10 amino
acids MHC class II accommodate peptides of >13 amino acids
CYTOSOL-DERIVED PEPTIDES ARE PRESENTED BY MHC-I FOR T-CELLS
14 Degradation of endogenous proteins
takes place in the proteasomes, they are presented on cell surface
by MHC I In the class I MHC pathway, protein antigens in the
cytosol are processed by the proteasomes. The mechanisms of antigen
processing are designed to generate peptides that have the
structural characteristics required for associating with MHC
molecules and to place these peptides in the same cellular location
as the appropriate MHC molecules with available peptide-binding
clefts. Peptides generated in the cytosol are translocated by a
specialized transporter (transporter associated with antigen
processingTAP) into the ER, where newly synthesized class I MHC
molecules are available to bind the peptides. On the luminal side
of the ER membrane, the TAP protein associates with a protein
called tapasin. Peptides translocated into the ER bind to class I
MHC molecules that are associated with the TAP dimer through
tapasin. Stable peptide-class I MHC complexes that were produced in
the ER move through the Golgi complex and are transported to the
cell surface by exocytic vesicles. Once expressed on the cell
surface, the peptide-class I complexes may be recognized by peptide
antigen-specific CD8+ T cells. MHC do not recognize or distinguish
self and nonself peptides
Antigen presentation goes in the absence of pathogen or T cells as
well ! Displays intracellular antigens
MHCI Displays intracellular antigens to cytotoxic T cells Cytosolic
antigens are processed and displayed by class I MHC molecules,
which are expressed on all nucleated cellsagain, as expected,
because all nucleated cells can be infected with some viruses.
Class Iassociated peptides are recognized by CD8 + T lymphocytes,
which differentiate into CTLs. The CTLs kill the infected cells and
eradicate the infection, this being the most effective mechanism
for eliminating cytoplasmic microbes. Tc RECOGNITION OF ENDOGENOUS
ANTIGENES BY T-LYMPHOCYTES TCR Peptide
MHCI is expressed by all nucleated cells Peptides of endogenous
proteinsbind to class I MHC molecules presented to cytotoxic T
cells Tc TCR Peptide MHCI Endogenous Ag Ligation of the TCR by
MHC-peptide ligands results in the clustering of coreceptors (CD4
and CD8). CD4 and CD8 are T cell coreceptors that bind to
nonpolymorphic regions of MHC molecules and facilitate signaling by
the TCR complex. CD8 and CD4 interact with class I and class II MHC
molecules, respectively, and are responsible for the class I or
class II MHC restriction of these subsets of T cells. The Ig domain
of CD8 binds to the nonpolymorphic 3 domain of class I MHC
molecules. APC T cells MHCI, presentation of intracellular
pathogens
MHCII, presentation of extracellular pathogens antigen presenting
cells T cell receptor (TCR) T cell activation Cytotoxic T cells
Helper T cells System optimalization 2:
MHCI present the intracellular area. Next step, how could the MHC
molecules (and the T cells) monitor the extracellular enviroment?
MHCII Expressed by professional antigen presenting cells
Macrophage, dendritic cell, B cell STRUCTURE OF CLASS II MHC
MOLECULES PEPTIDE 2 1 2 1 MHCII molecules are expressed on
dendritic cells, B lymphocytes, macrophages, and a few other cell
types. This pattern of MHC expression is linked to the functions of
class I-restricted and class II-restricted T cells. Class II
molecules are expressed mainly on these cell types and provide a
system for display of peptides derived from extracellular microbes
and proteins. STRUCTURE OF CLASS II MHC MOLECULES
A polymorphic and a polymorphic chain 2 1 2 1 PEPTID PEPTIDE Class
II MHC molecules are composed of a polymorphic chain noncovalently
attached to a polymorphic chain. The amino-terminal 1 and 1
segments of the class II chains interact to form the
peptide-binding cleft, which is structurally similar to the cleft
of class I molecules. The 2 and 2 segments of class II molecules,
like class I 3 and 2-microglobulin, are folded into Ig domains. The
2 segment of class II molecules contains the binding site for CD4,
similar to the binding site for CD8 in the 3 segment of the class I
heavy chain. In class II molecules, the ends of the peptide-binding
cleft are open, so that peptides of 30 residues or more can fit. 1
and 1 domens are responsible for peptide binding 22 Cleft geometry
b2-M a-chain Peptide a-chain b-chain Peptide
MHC class I accommodate peptides of 8-10 amino acids MHC class II
accommodate peptides of >13 amino acids Presentation of
extracellular peptides by MHCII
In the class II MHC pathway, extracellular protein antigens are
endocytosed into vesicles, where the antigens are processed and the
peptides bind to class II MHC molecules. The initial steps in the
presentation of an extracellular protein antigen are the binding of
the native antigen to an APC and the internalization of the
antigen. Internalized proteins are degraded enzymatically in late
endosomes and lysosomes to generate peptides that are able to bind
to the peptide-binding clefts of class II MHC molecules. Class II
MHC molecules are synthesized in the ER and transported to
endosomes with an associated protein, the invariant chain (Ii),
which occupies the peptide-binding clefts of the newly synthesized
class II molecules. Within the endosomal vesicles, the Ii
dissociates from class II MHC molecules and antigenic peptides are
then able to bind to the available peptide-binding clefts of the
class II molecules . Class II MHC molecules are stabilized by the
bound peptides, and the stable peptide-class II complexes are
delivered to the surface of the APC, where they are displayed for
recognition by CD4+ T cells. 24 Displays extracellular
antigens
! ! MHCII Displays extracellular antigens to helper T cells T
lymphocytes, on the other hand, can see only peptide fragments of
protein antigens, and only when these peptides are presented by
specialized peptide display molecules on host cells. How can see T
cells the extracellular antigens? By segregating the class I and
class II pathways of antigen processing, the immune system is able
to respond to extracellular and intracellular microbes in different
ways best able to defend against these microbes. Extracellular
microbes are captured and ingested by APCs, including B lymphocytes
and macrophages, and are presented by class II molecules, which are
expressed mainly on these APCs (and on dendritic cells). Because of
the specificity of CD4 for class II, class IIassociated peptides
are recognized by CD4 + T lymphocytes, which function as helper
cells. These helper T cells help B lymphocytes to produce
antibodies, and they help phagocytes to destroy ingested microbes,
thereby activating the two effector mechanisms best able to
eliminate microbes that are internalized from the extracellular
environment. Neither of these mechanisms is effective against
viruses and other pathogens that survive and replicate in the
cytoplasm of host cells. 25 MHC do not recognize or distinguish
self and nonself peptides
Antigen presentation goes in the absence of pathogen or T cells as
well The two antigen presentation pathways function in a parallel
simultaneous way A type of MHC molecule presents a lot of different
peptides in the same time. Most likely only a few of them, if any,
derived form pathogen. (one MHC molecule present only one peptide,
millions of MHC present several thousand different peptides) 26
Antigen presentation by MHCII:
Requires professional antigen presenting cells Exogen antigens
Helper T cells CD4+ cells 27 RECOGNITION OF EXOGENOUS ANTIGENES BY
HELPER T-LYMPHOCYTES
Th Peptides of exogenous proteins (toxin, bacteria, allergen) bind
to class II MHC molecules presented to helper T cells TCR Peptide
MHCII Exogenous Ag Once expressed on the APC surface, the
peptide-class II complexes are recognized by peptide
antigen-specific CD4+ T cells, with the CD4 coreceptor playing an
essential role by binding to nonpolymorphic regions of the class II
molecule. CD4 protein binds to the nonpolymorphic 2 domain of the
class II MHC molecule. T cells MHCI, presentation of intracellular
pathogens
MHCII, presentation of extracellular pathogens antigen presenting
cells T cell receptor (TCR) T cell activation Cytotoxic T cells
Helper T cells Macrophage, dendritic cell, B cell
MHCII Expressed by professional antigen presenting cells
Macrophage, dendritic cell, B cell PEPTIDE 2 1 2 1 Macrophage, DC
MHCII Exogen Ag Fagocytosis PRR or opsonization Degradation of
Patogen in the lysosome Peptide MHCII connection APC Dendritic
cells are resident in epithelia and tissues capture protein
antigens and transport the antigens to draining lymph nodes. During
this migration, the dendritic cells mature and become efficient
APCs. DCs use receptors to capture and endocytose microbes and
their antigens and then process the ingested proteins into peptides
capable of binding to MHC molecules. In cell-mediated immune
responses, macrophages present the antigens of phagocytosed
microbes to effector T cells, which respond by activating the
macrophages to kill the microbes. Circulating monocytes are able to
migrate to any site of infection and inflammation, where they
differentiate into macrophages and phagocytose and destroy
microbes. CD4+ T cells recognize microbial antigens being presented
by the macrophages and provide signals that enhance the
microbicidal activities of these macrophages. Constitutive checking
of the extracellular enviroment (fagocytosis, pinocytosis) 31 B
cell-mediated antigen presentation
In humoral immune responses, B lymphocytes internalize protein
antigens and present peptides derived from these proteins to helper
T cells. This antigen-presenting function of B cells is essential
for helper T cell-dependent antibody production. B cell-mediated
antigen presentation
B lymphocytes migrate from one secondary lymphoid organ to the next
in search of antigen. The activation of antigen-specific B
lymphocytes is initiated by the binding of antigen to membrane Ig
molecules, which, in conjunction with the associated Ig and Ig
proteins, make up the antigen receptor complex of mature B cells.
Antibody responses to protein antigens require recognition and
processing of the antigen by B cells, followed by presentation of a
peptide fragment of the antigen to helper T cells, leading to
cooperation between the antigen-specific B and T lymphocytes.
Antigen-activated helper T cells and B cells move toward one
another in response to chemokine signals and make contact. In this
location, the B cell presents antigen to the T cell, and the B cell
receives activating signals from the T cell. Summary of APCy
Represent the extracellular enviroment
The presentation of cytosolic versus vesicular proteins by the
class I or class II MHC pathways, respectively, determines which
subsets of T cells will respond to antigens found in these two
pools of proteins and is intimately linked to the functions of
these T cells. Represent the extracellular enviroment Represent the
intracellular enviroment RECOGNITION OF EXOGENOUS AND ENDOGENOUS
ANTIGENES BY T-LYMPHOCYTES
Peptides of endogenous proteins (virus, tumor) bind to class I MHC
molecules presented to cytotoxic T cells Th Peptides of exogenous
proteins (toxin, bacteria, allergen) bind to class II MHC molecules
presented to helper T cells Tc TCR Peptide MHCI TCR Peptide MHCII
Endogenous Ag Exogenous Ag Endogenously synthesized antigens, such
as viral and tumor proteins, are located in the cytoplasm and are
recognized by class I-restricted CD8+ CTLs, which kill the cells
producing the intracellular antigens. Conversely, extracellular
antigens usually end up in endosomal vesicles and activate class
II-restricted CD4+ T cells because vesicular proteins are processed
into class II-binding peptides. CD4+ T cells function as helpers to
stimulate B cells to produce antibodies and macrophages to enhance
their phagocytic activity, both mechanisms that serve to eliminate
extracellular antigens. Thus, antigens from microbes that reside in
different cellular locations selectively stimulate the T cell
responses that are most effective at eliminating that type of
microbe. This is especially important because the antigen receptors
of CTLs and helper T cells cannot distinguish between extracellular
and intracellular microbes. By segregating peptides derived from
these types of microbes, the MHC molecules guide CD4+ and CD8+
subsets of T cells to respond to the microbes that each subset can
best combat. APC T cells MHCI, presentation of intracellular
pathogens
MHCII, presentation of extracellular pathogens T cell receptor
(TCR) Structure Comparision with BCR T cell activation Cytotoxic T
cells Helper T cells The TCR, which recognizes peptide antigens
displayed by MHC molecules
T cell receptor (TCR) The TCR, which recognizes peptide antigens
displayed by MHC molecules BCR s C H2 H3 V L H H1 The TCR, which
recognizes peptide antigens displayed by MHC molecules, is a
membrane-bound heterodimer composed of an chain and a chain. Each
chain containing one variable (V) region and one constant (C)
region. The V and C regions are homologous to immunoglobulin V and
C regions. Both the chain and the chain of the TCR participate in
specific recognition of MHC molecules and bound peptides! Antigen
recognition is similar for B and T lymphocyte receptors but also
differs in important ways. Antibodies can bind many different types
of chemical structures, often with high affinities, which is why
antibodies can bind to and neutralize many different microbes and
toxins that may be present at low concentrations in the
circulation. TCRs only recognize peptide-MHC complexes and bind
these with relatively low affinity, which may be why the binding of
T cells to APCs has to be strengthened by additional cell surface
adhesion molecules. The three-dimensional structure of the TCR is
similar to that of the Fab region of an Ig molecule. Unlike in
antibodies, both TCR chains are anchored in the plasma membrane;
TCRs are not produced in a secreted form and do not undergo class
switching or affinity maturation during the life of a T cell.
Membrane-bound heterodimer composed of an chain and a chain, each
chain containing one variable (V) region and one constant (C)
region Both the chain and chains of the TCR participate in specific
recognition of MHC molecules and bound peptides The antigen
receptor of MHC-restricted CD4+ helper T cells and CD8+ cytotoxic T
lymphocytes (CTLs) is a heterodimer consisting of two transmembrane
polypeptide chains, designated TCR and , covalently linked to each
other by a disulfide bridge between extracellular cysteine
residues. These T cells are called T cells. A less common type of
TCR, found on T cells, is composed of TCR and chains. The CD3
proteins are noncovalently associated with the TCR heterodimer, and
when the TCR recognizes antigen, these associated proteins
transduce the signals that lead to T cell activation. CD3 CD3 T
cell receptor and its signal transduction units
Both and chains continue into short hinge regions, which contain
cysteine residues that contribute to a disulfide bond linking the
two chains. These residues interact with negatively charged
residues present in the transmembrane portions of other
polypeptides (those of the CD3 complex and ) that are part of the
TCR complex. The CD3 and proteins are noncovalently associated with
the TCR heterodimer, and when the TCR recognizes antigen, these
associated proteins transduce the signals that lead to T cell
activation. The CD3 , , and proteins are homologous to each other.
Each TCR complex contains one TCR heterodimer associated with one
CD3 heterodimer, one CD3 heterodimer, and one disulfide-linked
homodimer. T cells MHCI, presentation of intracellular
pathogens
MHCII, presentation of extracellular pathogens T cell receptor
(TCR) Structure Comparision with BCR T cell activation Cytotoxic T
cells Helper T cells TCRs only function as membrane receptors
B cell Plasma cell TCR Properties of antibodies and T cell antigen
receptors (TCRs): Antibodies (also called immunoglobulins) may be
expressed as membrane receptors or secreted proteins; TCRs only
function as membrane receptors. When immunoglobulin (Ig) or TCR
molecules recognize antigens, signals are delivered to the
lymphocytes by proteins associated with the antigen receptors. Note
that single antigen receptors are shown recognizing antigens, but
signaling typically requires the binding of two or more receptors
to adjacent antigen molecules. Antibodies serve different functions
at different stages of humoral immune responses: membrane-bound
antibodies on B cells recognize antigens to initiate the responses,
and secreted antibodies neutralize and eliminate microbes and their
toxins in the effector phase of humoral immunity. In cell-mediated
immunity, the effector function of microbe elimination is performed
by T lymphocytes themselves and by other leukocytes responding to
the T cells. The antigen receptors of T cells are involved only in
antigen recognition and T cell activation, and these proteins are
not secreted and do not mediate effector functions. T cell TCR has
a single antigen recognition unit Citotoxicity Citokine
production
Since there is no soluble TCR, effector funcions are mediated by
the T cells itself: Citotoxicity Citokine production CD8+ CTLs
eliminate intracellular microbes mainly by killing infected cells.
In addition to direct cell killing, CD8+ T cells secrete IFN- and
thus contribute to macrophage activation in host defense and in
hypersensitivity reactions. Effector T cells of the CD4+ lineage
function by secreted cytokines and cell surface molecules to
activate other cells to eliminate microbes. CD4+ T cells also
participate indirectly in host defense by helping B lymphocytes to
produce high-affinity antibodies against extracellular microbes and
by promoting the development of fully functional CTLs that combat
intracellular microbes such as viruses. CHARACTERISTICS OF T-CELL
ANTIGEN RECOGNITION
Antigen receptor T-CELL B-CELL CHARACTERISTICS OF T-CELL ANTIGEN
RECOGNITION The TCR is not able to interact directly with soluble
or cell-bound antigen T-cell activation can be induced by antigen
in the presence of acessory cells, only ACCESSORY CELL NO
INTERACTION ANTIGEN BINDING T-CELL ACTIVATION V C a/b II ANTIGEN
RECOGNITION BY T-CELLS REQUIRES
PEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS THAT EXPRESS MHC
MOLECULES T II Cell surface MHC-peptide complex T-cell response
soluble Ag Peptide antigen Native membrane Ag Cell surface peptides
APC T lymphocytes recognize peptide antigens that are bound to and
displayed bymajor histocompatibility complex (MHC) molecules of
antigen-presenting cells. T cell receptor recognizes a complex of
peptide antigen displayed by a MHCmolecule. Major
histocompatibility complex (MHC) molecules are expressed
onantigen-presenting cells and function to display peptides derived
from proteinantigens. The cells that capture microbial antigens and
display them for recognition by Tlymphocytes are called
antigen-presenting cells (APCs). APC APC No T-cell response B cell
epitope T cell epitope recognized by B cells proteins
polysaccharides lipids DNA steroids etc. (many artificial
molecules) cellor matrix associated or soluble recognized byT cells
proteins mainly (8-23 amino acids) requires processing by APC
TCR-BCR similarity: Immunglobulin domain structure
VDJ ---- numerous, randomly generated specificity One cell carries
only one specificity Antigen presence--- initiates the clonal
expansion of the cells that recognizes it Daughter cells have the
same specificity (affinity maturation in B cells) as the progenitor
Cells that recognizes self antigen are eliminated in the primary
lymphatic tissues (bone marrow, thymus) But TCR do not recognize
free antigen, only MHC peptide complex Recognizes only protein
antigens No soluble form TCR has a single antigen recognition unit
Other effector functions: BCR TCR Neutralization Citotoxicity
Opsonization, increase phagocytosis (Citokine production)
complement activation NK-cell activation T cells MHCI, presentation
of intracellular pathogens
MHCII, presentation of extracellular pathogens T cell receptor
(TCR) T cell activation Cytotoxic T cells Helper T cells Macfarlane
Burnet (1956 - 1960) CLON SELECTION HYPOTHESIS
Antibodies are natural products that appear on the cell surface as
receptors and selectively react with the antigen Lymphocyte
receptors are variable and carry various antigen-recognizing
receptors Non-self antigens/pathogens encounter the existing
lymphocyte pool (repertoire) Antigens select their matching
receptors from the available lymphocyte pool, induce clonal
proliferation of specific clones and these clones differentiate to
antibody secreting plasma cells The clonally distributed
antigen-recognizing receptors represent about ~107 109 distinct
antigenic specificities Macfarlane Burnet (1956 - 1960) CLON
SELECTION HYPOTHESIS
Lymphocytes are monospecific cells Antigen engagement result in the
activation of lymphocytes Activated lymphocytes differentiate and
proliferate but keep their antigen specificity Lymphocytes reacting
with self antigen during their development in the primary lymphoid
organs, become inactivated or die by apoptosis. ! ! TCR can
recognize only the MHC peptide komplex
A portion of the bound peptide is exposed from the open top of the
cleft of the MHCmolecule, and the amino acid side chains of this
portion of the peptide are recognizedby the antigen receptors of
specific T cells. The same T cell receptor also interactswith
polymorphic residues of the helices of the MHC molecule itself. T
cell response requires the DC-mediated antigen presentation in the
secondary lymphoid organs
Antigens that are transported by dendritic cells to the secondary
lymphoid organs (e.g. lymph nodes) are recognized by naive T
lymphocytes that recirculate through these lymph nodes. The T cells
are activated to differentiate into effector and memory cells,
which may remain in the lymphoid organs or migrate to nonlymphoid
tissues. At sites of infection, the effector cells are again
activated by antigens and perform their various functions, such as
macrophage activation. Antigen recognition of T cells Antigen
recognition of T cells
Protein degradation to peptide Peptide-MHC association Peptide/MHC
complex expression on the cell surface TCR recognizes the
peptide/MHC complex Antigen presenting cell T cell MHC RESTRICTION
The reason that T cells recognize only peptides is that the antigen
receptors of CD4+ and CD8+ T cells are specific for antigens that
are displayed by MHC molecules, and these molecules can bind
peptides but no other chemical structures. Thus, every T cell is
specific for a combination of amino acid residues of a peptide
antigen plus portions of the MHC molecule. MHC molecules are highly
polymorphic, and variations in MHC molecules among individuals
influence both peptide binding and T cell recognition. A single T
cell can recognize a specific peptide displayed by only one of the
large number of different MHC molecules that exist. This phenomenon
is called MHC restriction. One single T-cell receptor can recognize
a given MHC peptide complex The TCR-specific peptide is recognized
only when its presented with an MHC on which the TCR had been
selected during its development in the thymus If the peptide binds
to another MHC molecule no T-cell recognition occurs (by this T
cell) If the same MHC molecule binds another peptide, no T-cell
recognition occurs Distinct T cell receptors from different
microbes
Specificity of innate immunity Specificity of T cells Tc APC peptid
MHC Distinct T cell receptors Peptides derived from different
microbes ( ) Specificity of innate immunity Specificity of T cells
Tc
direct connetion between innate cells and pathogen ( ) Specificity
of T cells Tc APC peptid MHC No direct connetion between T cell and
pathogen APC-T cell connection Distinct T cell receptors The
restriction of T cell recognition to MHC-associated peptides
ensures that T cells see and respond only to cell-associated
antigens. This is because MHC molecules are cell membrane proteins,
and because peptide loading and subsequent expression of MHC
molecules depend on intracellular biosynthetic and assembly steps.
In other words, MHC molecules can be loaded with peptides only
inside cells, where intracellular and ingested antigens are
present. Therefore, T lymphocytes can recognize the antigens of
intracellular microbes, which require T cellmediated effector
mechanisms, as well as antigens ingested from the extracellular
environment, such as those against which antibody responses are
generated. Peptides derived from different microbes Phases of T
cell response
(review) Phases of T cell response T cell response The
proliferation of T cells is restricted to the secondary lymphoid
organs. Antigen is delivered to these organs by DCs IL-2 is the
main AUTOKRINE growth factor for T-cells.High affinity IL-2 Rec
also upregulated. A similar APC-produced cytokine, IL-15,
stimulates proliferation of CD8+ cells, especially memory cells of
the CD8+ subset. BEFORE ANTIGEN EXPOSURE frequency of naive T cells
specific for any antigen is 1 in 105 to 106 lymphocytes..AFTER
clonal expansion this frequency of all CD8+ T cells specific for
that microbe may increase to about 1 in 3 to 1 in 10, representing
a >50,000-fold expansion of antigen-specific CD8+ T cells and
the number of specific CD4+ cells increases to 1 in 100 to about 1
in 1000 lymphocytes. Studies in mice first showed this tremendous
expansion of the antigen-specific population in some acute viral
infections and, remarkably, it occurred within as little as 1 week
after infection. Equally remarkable was the finding that during
this massive antigen-specific clonal expansion, "bystander" T cells
not specific for the virus did not proliferate. Many of the progeny
of the antigen-stimulated cells differentiate into effector cells.
Effector cells are short-lived, and the numbers of antigen-specific
T cells rapidly decline as the antigen is eliminated. After the
immune response subsides, the surviving memory cells specific for
the antigen number on the order of 1 in 104. T cells MHCI,
presentation of intracellular pathogens
MHCII, presentation of extracellular pathogens T cell receptor
(TCR) T cell activation Cytotoxic T cells Helper T cells CITOTOXIC
T LYMPHOCYTES
cytotoxic T cells CTLs kill targets that express the same class
I-associated antigen that triggered the proliferation and
differentiation of naive CD8+ T cells from which they are derived
and do not kill adjacent uninfected cells that do not express this
antigen. Infected or tumoric cells T lymphocytes recognize
virus-infected cells virus KILLING OF TUMOR CELLS BY CTL
Cytotoxic T lymphocytes recognize virus-infected or tumor cells The
CTL binds and reacts to the target cell by using its antigen
receptor, coreceptor (CD8), and adhesion molecules. Within a few
minutes of a CTL's antigen receptor recognizing its antigen on a
target cell, the target cell undergoes changes that induce it to
die by apoptosis. CTLs kill target cells by two main mechanisms:
Complexes of perforin and granzymes are released from the CTL by
granule exocytosis and enter target cells. The granzymes are
delivered into the cytoplasm of the target cells by a
perforin-dependent mechanism, and they induce apoptosis. FasL is
expressed on activated CTLs, engages Fas on the surface of target
cells, and induces apoptosis. After delivering the lethal hit, the
CTL is released from its target cell, which usually occurs even
before the target cell goes on to die. T cells MHCI, presentation
of intracellular pathogens
MHCII, presentation of extracellular pathogens T cell receptor
(TCR) T cell activation Cytotoxic T cells Helper T cells Th1 Th2
Th17 T cells of the CD4+ lineage function by secreted cytokines and
cell surface molecules to activate other cells to eliminate
microbes. CD4+ T cells also participate indirectly in host defense
by helping B lymphocytes to produce high-affinity antibodies
against extracellular microbes and by promoting the development of
fully functional CTLs that combat intracellular microbes such as
viruses. In general, TH1 cells activate macrophages, TH17 reactions
are dominated by neutrophils (and variable numbers of macrophages),
and TH2 cells recruit and activate eosinophils. Each type of
leukocyte is specially adapted to destroy particular types of
microbes. This cooperation of T lymphocytes and other leukocytes
illustrates an important link between adaptive and innate immunity.
There are three distinct subsets of CD4+ T cells, called TH1, TH2,
and TH17, that function in host defense against different types of
infectious pathogens and are involved in different types of tissue
injury in immunologic diseases. The defining characteristics of
differentiated subsets of effector cells are the cytokines they
produce. The signature cytokines produced by the major CD4+ T cell
subsets are IFN- for TH1 cells; IL-4, IL-5, and IL-13 for TH2
cells; and IL-17 and IL-22 for TH17 cells Recognition of the
presented antigen induces cytokine production of helper T
cells
CD4+ T cells recognize antigens of phagocytosed and extracellular
microbes and produce cytokines that activate the phagocytes to kill
the microbes and stimulate inflammation. CD8+ T cells can also
secrete cytokines and participate in similar reactions. CD8+
cytotoxic T lymphocytes (CTLs) recognize antigens of microbes
residing in the cytoplasm of infected cells and kill the cells.
EFFECTOR CD4+ HELPER T LYMPHOCYTES SECRETE DIFFERENT
CYTOKINES
IL-4, IL-5, IL-10 Th2 Th0 IFN, IL-2, TNF-/LT Th1 IFN IL-4
Differentiated TH1, TH2, and TH17 cells all develop from naive CD4+
T lymphocytes, mainly in response to cytokines present early during
immune responses, and differentiation involves transcriptional
activation and epigenetic modification of cytokine genes. The
cytokines that drive the development of CD4+ T cell subsets are
produced by APCs (primarily dendritic cells and macrophages) and
other immune cells (such as NK cells and basophils or mast cells)
present at the site of the immune response. Differentiation of each
subset is induced by the types of microbes which that subset is
best able to combat. Each subset of differentiated effector cells
produces cytokines that promote its own development and may
suppress the development of the other subsets. Inflammatory
cytokines CELLULAR IMMUNE RESPONSE Anti-inflammatory cytokines
HUMORAL IMMUNE RESPONSE T cells MHCI, presentation of intracellular
pathogens
MHCII, presentation of extracellular pathogens T cell receptor
(TCR) T cell activation Cytotoxic T cells Helper T cells Th1 Th2
Th17 Effector function of TH1 cells
IFN- is the principal macrophage-activating cytokine and serves
critical functions in immunity against intracellular microbes:
activates macrophages to kill phagocytosed microbes acts on B cells
to promote switching to certain IgG subclasses (IgG2a or IgG2c) and
to inhibit switching to IL-4-dependent isotypes (IgE) promotes the
differentiation of CD4+ T cells to the TH1 subset and inhibits the
differentiation of TH2 and TH17 cells. stimulates expression of
several different proteins that contribute to enhanced
MHC-associated antigen presentation CD4+ TH1 cells activate
macrophages by contact-mediated signals delivered by CD40L-CD40
interactions and by IFN-. They stimulate inflammation through the
secretion of cytokines, mainly TNF, IL-1, and chemokines, and
short-lived lipid mediators such as prostaglandins, leukotrienes,
and platelet-activating factor. The collective action of these
macrophage-derived cytokines and lipid mediators is to recruit more
leukocytes, which improves the ability to destroy infectious
organisms. T cells MHCI, presentation of intracellular
pathogens
MHCII, presentation of extracellular pathogens T cell receptor
(TCR) T cell activation Cytotoxic T cells Helper T cells Th1 Th2
Th17 Effector function of TH2 cells
TH2 cells stimulate IgE- and eosinophil-mediated reactions that
serve to eradicate helminthic infections. TH2 cells secrete IL-4,
IL-5, and IL-13, which work cooperatively to eradicate these
infections. Roles of TH2 Cells in Host Defense: IgE- and
eosinophil-mediated reactions. IL-4 (and IL-13) stimulates the
production of helminth-specific IgE antibodies, which opsonize the
helminths and promote the binding of eosinophils. IL-5 activates
the eosinophils and these cells release their granule contents,
which are capable of destroying even the tough integuments of
helminths. Activation of mast cells. Mast cells express
high-affinity Fc receptors and may be activated by IgE-coated
helminths and other antigens that bind IgE, resulting in
degranulation. The granule contents of mast cells include
vasoactive amines, and mast cells secrete cytokines such as TNF and
chemokines, and lipid mediators, all of which induce local
inflammation that helps to destroy the parasites. Barrier immunity.
Cytokines produced by TH2 cells are involved in blocking entry and
promoting expulsion of microbes from mucosal organs. For instance,
IL-13 stimulates mucus production, and IL-4 and IL-13 may stimulate
peristalsis in the gastrointestinal system. Thus, TH2 cells play an
important role in host defense at the barriers with the external
environment, sometimes called barrier immunity. Alternative
macrophage activation. IL-4 and IL-13 activate macrophages to
express enzymes that promote collagen synthesis and fibrosis. The
macrophage response to TH2 cytokines has been called alternative
macrophage activation to distinguish it from the activation induced
by IFN-. Macrophages that are activated by TH2 cytokines contribute
to tissue remodeling and fibrosis in the setting of chronic
parasitic infections and allergic disease. Alternatively activated
macrophages may also serve to initiate repair after diverse types
of tissue injury that may not involve infectious agents or immune
responses; in these situations, the activating cytokines, such as
IL-4, may be produced by eosinophils and other cell types in
tissues. Alternatively activated macrophages induce the formation
of fibrous tissue by secreting growth factors that stimulate
fibroblast proliferation (platelet-derived growth factor), collagen
synthesis (transforming growth factor- [TGF-]), and new blood
vessel formation or angiogenesis (fibroblast growth factor). TH2
cytokines suppress classical macrophage activation and interfere
with protective TH1-mediated immune responses to intracellular
infections. Suppression of classical macrophage activation is, in
part, because IL-4 stimulates production of cytokines such as IL-10
and TGF- that inhibit TH1 development and function. T cells MHCI,
presentation of intracellular pathogens
MHCII, presentation of extracellular pathogens T cell receptor
(TCR) T cell activation Cytotoxic T cells Helper T cells Th1 Th2
Th17 TH17 cells secrete cytokines that recruit leukocytes, mainly
neutrophils to sites of infection. Neutrophils are a major defense
mechanism against extracellular bacteria and fungi, TH17 cells play
an especially important role in defense against these infections.
Effector function of TH17 cells
IL-1 and IL-6 produced by APCs and transforming growth factor-
(TGF-) produced by various cells activate the transcription factors
(RORt and STAT3) which stimulate the differentiation of naive CD4+
T cells to the TH17 subset. IL-23, which is also produced by APCs,
especially in response to fungi, stabilizes the TH17 cells. TGF-
may promote TH17 responses indirectly by suppressing TH1 and TH2
cells, both of which inhibit TH17 differentiation. IL-21 produced
by the TH17 cells amplifies this response. EFFECTOR T
LYMPHOCYTES
Cytotoxic+ T-cells EFFECTOR T LYMPHOCYTES MHCI is present in all
the nucleated cells
Intracellular pathogens can be presented on all the cells Any cell
is infected, can be killed by cytotoxic T cells MHCII present
extracellular antigens to helper T cells. Helper T cells direct the
immune response by the pruduced cytokines.