Transcript Immunol-revision-lecture-3-prof-feighery

Immunology
nd
2
Med 2009
Some revision points
Con Feighery
Lecture content
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How to recognise T cells and B cells
Structure of the T cell receptor
The different types of T cells
The role of MHC in activation of T cells
How cytokines influence the immune system
Monocytes / macrophages
Ingested antigen is
presented
T cell
B cell
- help
- suppress
- kill
antibody
Antigen presenting cells - APC
• Macrophages
• Dendritic cells
• B cells
Dendritic cell
B cell identification
B cells have a specific receptor
for antigen
antibody molecule
B cell identification
B cells have a specific receptor
for antigen
antigen can bind directly
to this receptor
T cell identification
T cells have a specific receptor
for antigen
TCR = T cell receptor
CD3 on T cells
CD3 molecule bound to TCR
CD3 signals to cell interior
T cell receptor - 2 chains
alpha chain
beta chain
TCR - alpha, beta chains
constant region
variable region
alpha chain
beta chain
variable region
TCR - alpha, beta chains
constant region
variable region
variable region
The shape of the variable region
binds to the shape of different
antigens.
T helper cells CD4+ T cells
CD4 molecules on T helper cells
T cytotoxic cells CD8+ T cells
CD8 molecules on T cytotoxic cells
T cell molecules
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T cell receptor = TCR
CD3 - signaling molecule
CD4 - on T helper cells
CD8 - on T cytotoxic cells
• “CD” = cluster of differentiation - used in
describing many molecules of immune system
For T cells to function ….
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Need TCR - binds antigen
Need CD3 - signals binding
Need antigen to be “presented” APC
Antigen has to be bound to “MHC” mols.
Co-stimulation signal to T cell ….
MHC molecules
Major Histocompatability Complex = MHC
• 2 types
• MHC class I
• MHC class II
• Enable T cells to react with antigen
• MHC = transplantation antigens - also called
HLA molecules = human leucocyte antigens
CD8+ T cells - MHC I interaction
CD8
T cytx
TARGET
APC
CELL
CD8+ T cells interact with antigen bound to MHC class I
The CD8 molecule binds exclusively to MHC class I
CD8+ T cells can kill target cells by inserting a ‘perforating
hole’ in the cell, through which enzymes enter, damaging
the cell
CD8
TARGET
APC
CELL
T cytx
• perforin
• enzymes
MHC class I
• Found on all cells in the body
• Essential for function of T cytotoxic cells
• Viral peptides bind to MHC I
Top end of a MHC class I molecule
Don Wiley, died 2001
Scientist,
crystallographer
I'm sorry, but I just don't understand anything in biology
unless I know what it looks like.'
Don Wiley - appreciation
"Wiley was a crystallographer: this is the ultimate
molecular biology. ...The image of a class I MHC
protein with its peptide cargo firmly in place will
stand as a landmark Wiley discovery that forever
changed the field of immunology.…”
CD4+ T cells - MHC II interaction
CD4
APC
Th
MHC II
with peptide
CD4+ T cells - MHC II interaction
CD4
Th
CD4+ T cells interact with antigen bound to MHC
class II molecules
APC
MHC class II
Found on few cells in body • Macrophages
• Dendritic cells
• B cells
All these cells present antigen = antigen
presenting cells or APC
MHC class II on APC
APC
MHC II
with peptide
MHC class II on B cells
B
MHC II
with peptide
antibody
B cells act as APC
Th
B
antibody
Structure of molecules of IS
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T cell receptor
MHC class I
MHC class II
Antibody molecules
Knowledge of these structures helps
understand how the immune system works !
Structure of molecules of IS
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T cell receptor
MHC class I
MHC class II
Antibody molecules
Knowledge of these structures helps
understand how the immune system works !
TCR - alpha, beta chains
constant region
variable region
alpha chain
beta chain
variable region
T cell receptor structure
Alberts et al.
TCR - gamma, delta chains
constant region
variable region
gamma chain
delta chain
variable region
Immunoglobulin super-family
Alberts et al.
Many molecules in the immune system have an Ig-like structure and
hence, belong to the “Ig superfamily”.
MHC I and II structure
Alberts
et al.
CYTOKINES
Cells of the immune system ‘talk’ to
each other by producing cytokines - like
‘text messages’ informing cells what
their function should be!
Cytokine products of cells
APC
Th
CD28 B7
IL-1
IL-2
Cytokine product of cells
APC
Th
CD28 B7
IL-1
IL-2
Cells interact through the production
and release of cytokines - these bind
to cells and affect their function
Cytokine products of cells
APC
Th
IL-1
IL-2
Receptors - cytokines bind to
specific cell receptors
Cytokines
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Small protein molecules c. 20,000 aa
Specific types produced by different cells
Bind to cells and affect cell function
Some are called “interleukins” or IL
IL-1 helps T cell activation
Th
APC
IL-1 produced
by APC
T cell co-stimulation
Essential to T cell activation, division
and replication
CD4+ T cells - activation requires 2
signals
CD4
APC
Th
CD28
B7
T cell receptor binding to antigen = signal 1
CD28 binds to B7 = signal 2
Activation of T cells
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Requires 2 signals
Signal 1 - TCR, MHC, antigen
Signal 2 - CD28 binding to B7
Both signals must be from the same APC
ONLY now can T cell proliferation start
Stimulated T cell - IL-2 produced
CD4
APC
Th
IL-2 receptor
CD28
B7
IL-2
IL-2 binds to receptor on cell - causes cell growth, division
IL-2 required for T cell growth
APC
Th
CD28 B7
IL-2
CTLA-4 - negative signal
CD4
APC
Th
CTLA-4
B7
T cell receptor binding to antigen = signal 1
CTLA-4 binds to B7 - inhibits stimulation
Bi-directional flow of cytokines
APC
Th
cytokines
CD4+ T cells interact with APC and other cells by
releasing cytokines. APC also release cytokines.
APC
Th
cytokines
The type of cytokines that are released are crucial to the
type of immune response which results
T cell cytokines affect B cells
B
Th
IL-4,5,6
T cell cytokines affect B cells
B
Th
IL-4, 5 and 6 all
involved in B cell
stimulation and Ig
production
IL-4, IL-5, IL-6
Lymph node - cartoon
Alberts et al.
Lymph node - histology
Lymphoid
follicles
Interferon gamma helps kill
intracellular infections
MO
Th
IFN-g activates
macrophage killing
mechanisms
TB
Interferon - gamma
IFN-g
Cytotoxic T cells
CD8+ T cells can kill target cells by inserting a ‘perforating
hole’ in the cell, through which enzymes enter, damaging
the cell
CD8
TARGET
APC
CELL
T cytx
• perforin
• enzymes
T cytotoxic cell - recognition of
antigen, role of CD8
CD8
virus
APC
T cytx
Target cell
MHC I
T cytotoxic cell reacting with virus antigen
presented by MHC class I molecule
T cytotoxic cell - cytolytic mechanism
Lytic granules
Granules - content
perforin,
enzymes
virus
APC
T cytx
Target cell
Enzymes, water, salts
perforin
Types of T helper cells
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Cytokine production by T helper cells varies
Effect on the immune system varies
Sub-types of T helper cells
Th1 cells – interferon gamma product
Th2 cells – IL-4, IL-5, IL-6
Th17 cells – IL-17
T regulatory cells – IL-10
Effect of antigens on APC
Different surface molecs
Various antigenic
stimuli
APC
Different cytokines
APC - effect on T cell response
TH 1
APC
IFN-g
TH 2
IL-4
T reg
IL-10
Cytokines and T cells
• Depending on the antigen, APC may produce
different sets of cytokines
• These cytokines determine the type of T cell
that proliferates
• Different types of T cells produce specific sets
of cytokines