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Antigen Recognition by T lymphocytes (Chapter 5)

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Title: Antigen Recognition by T lymphocytes (Chapter 5)


1
Antigen Recognition by T lymphocytes(Chapter 5)
B cells T cells
Similar structure Similar structure
Produced by gene rearrangement Produced by gene rearrangement
Each clone expresses a single species of antigen receptor Each clone expresses a single species of antigen receptor
Express bound and soluble receptors Express only membrane-bound receptors (TCR)
Receptors bind intact molecules Receptors bind denatured peptides bound to MHC
2
Antigen recognition by B-cells and T-cells
Antigen processing
B-cells
T-cells
Major Histocompatibility Complex (MHC) assembly
3
Antigen processing and presentation
T-cell receptor can recognize antigen only in the
form of denatured peptide bound to an MHC
molecule ? pathogen-derived proteins must be
first degraded (antigen processing), and then
assembled into peptideMHC complex and presented
to T-cells (antigen presentation).
4
Major Histocompatibility Complex (MHC) molecules
  • Glycoproteins expressed almost on all cells of
    the body
  • There are two main types of MHC molecules Type I
    and Type II
  • Type I are expressed on all cells of human body,
    except red blood cells, brain and kidney
  • Type II are expressed only on three cell types,
    co called Professional Antigen Presenting cells
    (APC) dendritic cells, macrophages, and B cells
  • MHC (HLA) molecules exhibit significant variation
    in human population ? the primary cause of graft
    rejection in transplantations. The reason that
    the first successful organ transplantation was
    kidney transplantation is that kidney express
    very low levels of MHC molecules, and thus they
    did not interfere during transplantation

5
Figure 32.1
6
T cells
  • T cells come in two different types, helper cells
    and cytotoxic (killer) cells. They are named
    after the thymus, an organ situated under the
    breastbone. T cells are produced in the bone
    marrow and later move to the thymus where they
    mature. 
  • Thymus is essential for development of T cells.
    In mice (known as nude mice, since they also lack
    hair) and humans with diGeorge's syndrome, the
    thymus fails to form fully and the result is a
    lack of T cells and a consequent severe
    immunodeficiency.

7
Nude mice cannot reject tumors and have been thus
used to test new anti-cancer therapies
  • The nude mice have a dysfunctional immune system,
    and can only live in a sterile environment.
  • They cannot reject any transplanted tissue,
    including tumors.
  • Nude mice are very useful in cancer research
    because injected human cancer cells can grow into
    tumors allowing new ways to test cancer
    therapies.

Nude mouse with transplanted rabbit skin
8
T cells express specific T cell receptors (TCR)
  • In addition to TCR, each T cell expresses on its
    surface a glycoprotein either CD4 or CD8.
  • CD4 and CD8 T cells have different functions.
  • The function of CD8 T cells is to kill
    virus-infected cells.
  • The function of CD4 T cells is to activate other
    immune cells.

1
2
3
9
Helper T cells (CD4 cells)
  • The main regulators of the immune defense. Their
    primary function is to release cytokines, which
    then activate other immune cells.
  • The primary task of CD4 T cells is to activate
    other immune cells. However, the helper T cells
    themselves must be first activated. This happens
    when a dendritic cell, macrophage or B cells
    present the antigen assembled into MHC class II
    complex to CD4 T cell this is called antigen
    presentation.
  • When the TCR of a helper T cell recognizes the
    antigen, the T cell is activated. Once activated,
    helper T cells start to divide and produce
    cytokines that activate B and T cells as well as
    other immune cells.

10
(No Transcript)
11
Killer T cells (CD8 cells)
  • Specialized in attacking cells of the body
    infected by viruses. It can also attack cancer
    cells. Their main function is to kill the
    infected cell.
  • The cytotoxic killer CD8 T cell has receptors
    that are used to search each cell that it meets.
    CD8 T cells recognize antigens assembled into MHC
    class I complexes. MHC class I are expressed on
    all cells of human body, except for the brain. If
    a cell is infected, it is swiftly killed by CD8
    (cytotoxic, killer) T cells.

12
T Cell Receptor (TCR)
  • The absence of a secreted form of T Cell Receptor
    (TCR), and the requirement for TCR recognition of
    both peptide and MHC, made its isolation and
    characterization much more difficult than that of
    BCR. Thus, the structure of the T cell receptor
    was not elucidated until the 1980s.
  • As T cells develop in the bone marrow, they
    rearrange TCR gene segments to produce a unique
    TCR.
  • Immature T cells then migrate to the thymus,
    where they mature and complete their development.
    In the absence of thymus, T cells could not be
    produced, and this would result in a severe
    immune deficiency (that would resemble AIDS,
    since the HIV virus specifically attacks and
    destroys helper T cells).

13
The T-cell receptor resembles a single
antigen-binding arm (Fab) of Ig
  • T-cell receptor is composed of two different
    peptide chains, and has one antigen binding site.
  • It is always membrane bound.
  • Each chain has a variable region that binds
    antigen, and a constant region.
  • During T-cell development, the variability in the
    V region is produced by gene rearrangement.

14
Structure of T-cell receptor
  • T-cell receptor consists of two different
    polypeptide chains
  • T-cell receptor a chain (TCRa), and T-cell
    receptor b chain (TCRb).
  • a and b chains are organized into variable
    regions (V regions) and constant regions (C
    regions).
  • T-cell receptor is anchored in the membrane by a
    hydrophobic cytoplasmic tail.
  • Va and Vb form the antigen-recognition site each
    T-cell receptor possesses only one
    antigen-binding site.

15
Three-dimensional structure of the T-cell
receptor showing the antigen complementarity
determining regions (CDRs)
  • The sequence variation in the a and b chains is
    clustered into regions of hypervariability.
  • These loops form the antigen binding site, and
    are called complementarity determining regions
    (CDRs).
  • The T-cell receptor V domains have three CDR
    loops, CDR1, CDR2 and CDR3.

16
Figure 3-3
T-cell receptor rearrangement occurring during
T-cell development in the thymus
a-chain locus Similar to the Ig light chain
contains V and J
b-chain locus Similar to the Ig heavy chain
contains V, J and D
17
There are two classes of T-cell receptor
ab gd
  • T-cells express either ab, or gd, but NEVER
    both.
  • T-cells bearing gd receptors represent only 1-5
    of the T-cells.
  • gd T-cells do not require MHC molecules.
  • The biological function of gd receptors is not
    well understood.

18
MHC molecules present the antigen to T cells
Helper T cells
19
CD4 and CD8 Molecules
  • T helper cells express CD4 but not CD8
  • T cytotoxic cells express CD8 but not CD4
  • CD4 and CD8 are associated in the membrane with
    the TCR.
  • Both CD4 and CD8 function as adhesion molecules
    CD4 binds to Class II MHC molecules and CD8
    binds to Class I MHC molecules.
  • Binding of the TCR to the peptide/MHC complex is
    greatly augmented if CD4 or CD8 are assisting.
    Their cytoplasmic domains may also allow for
    signal transduction to occur.
  • The signal-transduction property of CD4 and CD8
    is mediated through their cytoplasmic domains.

20
CD proteins (Clusters of differentiation)
  • CD proteins are glycoproteins that are expressed
    on human leukocytes there are more than 250
    different CD proteins expressed on human white
    blood cells.
  • Each type of leukocytes expresses different CD
    protein(s) on its surface ? CD proteins are used
    as markers for different types of leukocytes.
  • CD3 all T cells (helper and killer T cells)
  • CD4 Helper T cells (specifically destroyed by
    HIV virus)
  • CD8 Killer T cells
  • CD25 Regulatory (helper, CD4) T cells
  • CD56 NK cells
  • CD66 neutrophils
  • CD proteins are recognized by specific monoclonal
    antibodies and are used to classify different
    types of leukemia. 

21
There are two classes of MHC molecules MHC class
I Presents antigen of intracellular origin
(viruses) to CD8 T cells MHC class II Presents
antigen of extracellular origin (bacteria) to CD4
T cells
  • Molecular basis of the interactions specific
    protein-protein interactions between CD8
    glycoprotein and MHC class I, and between CD4 and
    MHC class II.
  • CD8 and CD4 molecules are also called T-cell
    co-receptors.

22
Two classes of T cells are specialized to respond
to intracellular (viral) and extracellular
(bacterial) infection
Intracellular (viruses) CD8 cytotoxic T
cells Extracellular (bacteria) CD4 helper T cells
INFECTION
TH1 cells activate macrophages to kill the
bacteria and produce cytokines
Helper CD4 T Cells Main function is to help
other immune cells to respond to extracellular
infection (bacteria)
TH2 cells Stimulate B cells to make antibodies
Cytotoxic CD8 T cells Main function is to kill
the cells infected with the virus
CD4 and CD8 molecules are glycoproteins
23
1
2
3
24
Generation of peptide antigens that are presented
by MHC molecules
  • Proteins derived from intracellular (viruses)
    and extracellular (bacteria) pathogens are
    generated in different cellular compartments.
  • Peptides derived from intracellular pathogens
    presented by MHC I class Formed in the cytosol
    (cytoplasm) by proteasome degradation, and
    delivered to the endoplasmic reticulum, where
    they bind the MHC class I. Then they are
    presented to CD8 cytotoxic cells.
  • Peptides derived from extracellular pathogens
    presented by MHC II class Taken up by
    phagocytosis and degraded by proteases in the
    lysosomes. The antigenic peptides produced
    associate with MHC class II in the vesicular
    system (lysosomes), and are then presented to CD4
    helper cells.

25
Formation and transport of peptides that bind to
MHC class I
Pathogen-derived intracellular proteins in
infected cells are degraded by proteasome, a
multi-protein complex with protease
activities. The generated peptides are
transported into the endoplasmic reticulum (ER),
which is accomplished by a protein called
transporter associated with antigen processing
(TAP). TAP is essential for export of the peptide
from cytosol to ER. In patient with Bare
Lymphocyte Syndrome, TAP is not functional ? no
peptide is transported to ER ? MHC class I are
not expressed ? high susceptibility to viral
infections. In the endoplasmic reticulum, the
generated peptides are bound to newly synthesized
and folded MHC class I molecules, which is aided
by chaperones. The MHC class I-peptide complex is
transported through Golgi to the plasma membrane.
26
Proteasome Selective protein degradation occurs
in the proteasome, a large protein complex in the
nucleus cytosol of eukaryotic cells.
In 2004, Irwin Rose from the University of
California, received the Nobel Prize for
discovery of the function of proteasome.
27
Formation and transport of peptides that bind to
MHC class II
Extracellular pathogens (bacteria) are engulfed
by endocytosis (smaller antigens) or by
phagocytosis (larger pathogens) by neutrophils
and macrophages. The engulfed proteins are
degraded by proteases in the phagolysosomes,
special vesicles formed by fusion of phagocytic
vesicles with lysosomes. In the phagolysosomes,
the generated peptides are bound to newly
synthesized and folded MHC class II
molecules. The MHC class II-peptide complex is
transported to the plasma membrane in outgoing
vesicles.
28
Comparison of antigen processing and presentation
by MHC class I and II molecules
29
Expression of MHC molecules on human cells
  • MHC class I
  • Expressed by almost all human cells
    constitutively (all the time).
  • Since all human cells are susceptible to viral
    infections, this enables comprehensive
    surveillance by CD8 T cells. The lowest levels
    occur on kidney cells and in the brain. This may
    be one reason why kidney transplants are among
    the most successful organ transplants, and that
    herpes virus can successfully hide in the brain
    without being recognized by the cells of the
    immune system.
  • MHC class II
  • Constitutively expressed on only a few cell
    types, which are cells specialized for the uptake
    and presentation of antigens (professional
    antigen-presenting cells dendritic cells,
    macrophages and B cells). Expression of MHC class
    II can be increased during immune response by
    cytokines and interferons. MHC class II are
    recognized by CD4 cells.

30
Human Leukocyte Antigen Complex
  • Antibodies used to identify the MHC molecules
    react white leukocytes (white blood cells) but
    not with erythrocytes (red blood cells), which
    lack the MHC molecules
  • MHC molecules are also called Human Leukocyte
    Antigen complex (HLA)

31
MHC and Transplantation
  • The cause of transplant rejection is recognition
    of foreign MHC antigens by T cells and activation
    of those T cells to become cytotoxic or helper T
    cells.
  • Tissue matching involves identifying MHC antigens
    on both donor and recipient cells and using donor
    cells with as many MHC alleles identical to those
    of the recipient as possible.
  • HLA matching is done by serological assays that
    use antibodies to HLA alleles to type donor and
    recipient cells.
  • HLA matching improves graft survival but does not
    prevent rejection, even in MHC-identical siblings
    (except for identical twins).
  • Improved success in transplantation is due to
    increasing technical expertise, the availability
    of transplant centers to do HLA matching and
    minimize organ delivery time, and the
    availability of immunosuppressive drugs that
    block T cell activation.
  • The fetus is an almost perfect allograft (
    transplanted organ). We do not understand why
    most pregnancies are not rejected even though
    half of the baby's antigens are foreign to the
    mother.

32
SUMMARY Chapter 5Antigen Recognition by T
Lymphocytes
  • T cells recognize antigens through T cell
    receptors (TCR).
  • T cell receptors are glycoproteins composed of V
    and C domains, similarly as immunoglobulins
    (Igs), and a membrane-spanning region.
  • There are two types of T-cell receptors one made
    up of a and b chains (expressed on most T cells),
    and another made up of g and d chains.
  • All four types of T-cell receptor chains (a, b, g
    and d) require DNA rearrangements in order to be
    expressed, similarly as Igs.
  • T-cell receptors differ from Igs in that they are
    expressed only as cell surface receptors and are
    not secreted as soluble proteins with effector
    functions (as Igs).

33
SUMMARY-continued
  • T cells expressing ab receptors recognize
    peptides presented by MHC molecules, which have
    degenerate peptide binding sites.
  • Cytotoxic CD8 T cells recognize peptides
    presented by MHC class I, while the helper CD4 T
    cells recognize peptides presented by MHC class
    II.
  • The role of CD8 cytotoxic cells is to kill cells
    that have become infected with a virus or some
    other intracellular pathogen.
  • The role of CD4 helper cells is to help other
    immune cells to respond to extracellular
    infection
  • TH2 cells stimulate B cells to make
    antibodies,
  • TH1 cells activate macrophages to kill the
    pathogen.

34
Summary-continued
  • Protein antigens from intracellular and
    extracellular sources are processed into peptides
    by two different pathways.
  • Peptides generated by proteasome from
    intracellular pathogens (viruses) enter ER where
    they bind MHC class I, and are then recognized by
    CD8 cytotoxic T cells. MHC class I are expressed
    by all cell types except for erythrocytes and the
    brain.
  • Extracellular pathogens are taken up by
    phagocytosis and degraded into peptides in the
    lysosomes, where they also bind MHC class II
    molecules. MHC class II molecules are expressed
    only on professional antigen presenting cells
    (APC) dendritic cells, macrophages, and B cells.
    They activate CD4 helper T cells.

35
Development of T Lymphocytes
  • (Chapter 7)
  • Development of T cells in bone marrow by gene
    rearrangement
  • Positive and negative selection of T cells in the
    thymus (analogy of the phase II in B cells
    elimination of self-reactive cells)

36
Development of T Lymphocytes
  • Similarly as B cells, T cells (lymphocytes)
    originate from bone marrow stem cells.
  • Another similarity with B cells is the gene
    rearrangement in order to produce antigen
    receptors.
  • However, in contrast to B cells that rearrange
    the Ig genes in bone marrow, T cells have to
    leave the bone marrow, and enter another primary
    lymphoid organ the thymus.
  • Another difference between B and T cells is that
    in T cells, there are no changes in TCR structure
    after activation with antigen (no somatic
    hypermutation or isotype switching)
  • Two lineages of T lymphocytes (T cells) develop
    in the thymus ab T cells
    (majority)
  • gd T cells (1-5 of all T cells dont need
    MHC molecules to recognize antigen)

37
T cells develop in the thymus
  • T cells develop in bone marrow, but in order to
    mature, they need to migrate to thymus
    thymus-(T)-dependent lymphocytes
  • Thymus is a primary lymphoid organ located in the
    upper thorax (chest), just above the heart.
  • Progenitor (precursor) T cells ( thymocytes)
    enter the thymus, where they mature. Mature T
    cells leave the thymus and enter the secondary
    lymphoid tissues, where they become activated
    after exposure to antigen, and differentiate into
    effector T cells.

Mature T cells enter the blood stream, and after
infection accumulate in the secondary lymphoid
tissues where they are activated.
T cells develop in bone marrow and then migrate
to thymus where they mature
38
Thymus
  • Essential organ for development of T cells. In
    mice (known as nude, since they also lack hair)
    and humans with diGeorge's syndrome, the thymus
    fails to form fully and the result is a lack of T
    cells and a consequent severe immunodeficiency.
  • The key function of the thymus is the selection
    of the T cell repertoire that the immune system
    uses to combat infections.
  • This involves selection of T cells that are
    functional (positive selection), and elimination
    of T cells that are auto-reactive (negative
    selection).
  • Cells that pass both levels of selection are
    released into the bloodstream to perform vital
    immune functions.
  • If the negative selection fails, auto-immune
    diseases may arise.
  • Thymus is most active in babies and children, and
    then starts gradually shrinking. This results in
    the decreased production of new T cells, and in
    the increased susceptibility to infection in
    older people.

39
Positive and negative selection of the ab T-cell
repertoire
  • During the first phase of T-cell development,
    thymus produces millions of TCR regardless of
    their antigen specificity only small portion of
    these TCR can interact with the MHC isoforms
    expressed by an individual ? will be able to
    respond to antigens presented by these MHC
    molecules
  • The second phase of T-cell development involves a
    critical examination of the receptors produced,
    and selection of those that can work effectively
    with the individuals own MHC molecules.
  • These selection processes involve only ab T
    cells, since gd cells do not require the MHC
    proteins.
  • The ab double-positive thymocytes undergo first
    a positive selection, to ensure selection of
    T-cells that recognize peptides presented by
    self-MHC molecules, and then a negative
    selection, to eliminate the T-cells that bind to
    self-peptides and self-MHC molecules too
    strongly, and could potentially be auto-reactive.

40
Positive selection
  • After T-cells are produced in bone marrow, they
    migrate to the thymus, where they undergo first
    the positive selection.
  • During the positive selection, only the
    thymocytes ( immature T cells) that can interact
    (bind) with self-MHC molecules of the individual
    are selected. The rest (95 of thymocytes)
    undergoes apoptosis, and is removed
    (phagocytosed) by macrophages present in the
    thymus.

41
Negative selection
  • Eliminates T cells that bind too strongly to the
    complexes of self-peptides and self-MHC molecules
    presented by the cells in the thymus. If not
    eliminated, these cells could cause autoimmune
    diseases and tissue damage.
  • The cells that interact with MHC molecules too
    strongly undergo apoptosis, and are engulfed by
    macrophages present in the thymus.
  • In contrast to the positive selection (that is
    mediated by the epithelial cells of the thymus),
    the negative selection is mediated by
    bone-marrow-derived dendritic cells and
    macrophages present in the thymus.
  • After the negative selection, the mature
    single-positive T cells leave the thymus and
    enter the blood circulation.

42
Positive and negative T cell selection
Only about 2 of all thymocytes ( immature T
cells in the thymus) survive the dual strictures
of positive and negative selection. One
prominent immunologist has described the role of
thymocyte selection as "preventing the harmful
and rejecting the useless" and it may help to
view it in this light. Negative selection helps
prevent autoimmunity, positive selection ensures
that the peripheral T cells will be useful (
will bind the self-MHC molecules).
43
T cells undergo activation and differentiation
into effector T cells in secondary lymphoid
tissues after encounter with antigen
  • Only a small fraction of naive T cells (mature T
    cells before they encounter antigen) survives the
    positive and negative selection, and leaves the
    thymus.
  • Mature naive T cells can re-circulate between
    blood and lymphoid tissues for many years (in
    contrast to B cells, which have shorter life
    span).
  • In secondary lymphoid tissues, T cells accumulate
    in T cell areas, where they become activated by
    their specific antigens.
  • Encounter with antigen induces the final stage of
    T cell development their differentiation into
    effector T cells. Some effector T cells stay in
    the lymphoid tissues (CD4-TH2 cells), while
    others migrate to site of infection (CD8TH1
    cells).

44
Figure 1-18
In lymphoid tissues, T cells accumulate in T cell
areas
Antigen
T cells
45
Effector T cells
  • In contrast to terminally differentiated B cells
    (plasma cells), there are several types of
    terminally differentiated effector T cells.
  • CD8 T cells Cytotoxic T cells
    (recognize MHC class I molecules)
  • CD4 T cells

Activation (cytokines)
TH1 helper cells (activate macrophages) TH2
helper cells (induce differentiation of B cells
into plasma cells and production of antibodies)
(recognize MHC II molecules)
46
Summary
  • T cells develop in bone marrow, where they
    produce TCR (ab cells).
  • After they are produced in bone marrow, immature
    T cells, thymocytes, migrate to the thymus, where
    they complete their maturation, and undergo
    positive and negative selection.
  • During positive selection, only thymocytes that
    can interact with self-MHC molecules are
    selected. The rest undergoes apoptosis.
  • During negative selection, thymocytes that
    interact with self-MHC complexes too strongly are
    eliminated. After negative selection, T cells
    leave the thymus, and circulate in blood for
    decades.
  • T cells become activated in T cell areas of the
    secondary lymphoid tissues
  • Activated T cells differentiate into effector T
    cells (CD8 ? cytotoxic T cells CD4 ? helper T
    cells.
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