Transcript T cell development and self tolerance PPT

Topic 7
T Cell Development, Repertoire
Selection and Immune
Self Tolerance
©Dr. Colin R.A. Hewitt
[email protected]
Why is a mechanism for repertoire selection
and self tolerance needed?
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Generation of the TcR repertoire involves many random mechanisms
The specificity of TcR in the immature repertoire is also random & will
include cells with receptors that are:
Self
antigen
recognition
T
T
T
T
APC
1. Harmful
2. Useless
3. Useful
Foreign
antigen
recognition
Self proteins enter the endogenous and exogenous
antigen processing pathways
Self cellular
proteins
Self serum
& cellular
proteins
Processing pathways do not distinguish self from non-self
Self peptides load onto MHC class I & II molecules
Purify stable MHCpeptide complexes
Fractionate and
microsequence
peptides
Acid elute
peptides
>90% of eluted peptides are derived from self proteins
Yet self antigens do not usually activate T cells
The immune system allows a limited degree
of self recognition
TcRs recognise the non-self peptide antigen and the self MHC molecule
MHC molecules RESTRICT T cell activation
But how do T cells learn how much self recognition is acceptable?
T cells are only allowed to develop if their TcR
recognise parts of self MHC
Explains why T cells of MHC haplotype A do not recognise
antigen specific presented by MHC haplotype B
MHC A
haplotype
T CELL
MHC A
haplotype
APC
MHC B
haplotype
APC
Wholly self-reactive and useless T cells are removed
MHC-restricted are retained
T
T
T
T
T T T
Y Y Y Y Y Y
Y Y
Y Y Y YYYYY
Y YY
T
T
T
T
T
Y
T
T
Y
?
Harmful
Negatively
select
T
THYMUS
T
T
Y
T
T
T
Y
Random TcR
repertoire
ensures diversity
APC
Useless
Useful
Neglect
Positively
select
The thymus
Lobulated structure with a STROMA of epithelial cells & connective tissue
Stroma provides a microenvironment for T cell development & selection
Lobules differentiated into an outer CORTEX & inner MEDULLA, both
filled with bone-marrow-derived THYMOCYTES
Thymocyte
Cortex
Cortical
epithelial cell
Dendritic cell
Macrophage
Medulla
Medullary
epithelial cell
The thymus is required for T cell maturation
Athymic mice (nude) and humans (DiGeorge syndrome)
are immunodeficient due to a lack of T cells
Neonatal thymectomy
Thymus intact
No mature T cells
In adult
Mature T cells
In adult
Roles of the bone marrow and thymus in T cell
maturation
Defective lymphocyte
production
Normal thymus
scid/scid
No mature T cells
In adults
Thymus defect
Normal bone
marrow
nu/nu
No mature T cells
In adults
Bone marrow supplies T cells, and they mature
in the thymus
Marrow defect
Thymus defect
Bone marrow transplant
Thymus colonised by thymocytes from
thymus defective, i.e. orange, mouse
Thymus graft
Thymus colonised by thymocytes from the
thymus defective, i.e. orange, mouse
The thymus matures T cells after
birth, but early in life
Remove Thymus
Adult
Neonate
T cells not yet left thymus
Mature T & B cells
No T cells
Mature B cells present
The thymus is needed to generate mature T cells
The thymus is most active in the foetal
and neonatal period
OVA
Adult
KLH
Neonate
T cells vs. OVA
No T cells vs.OVA
T cells vs. KLH
T cells vs. KLH
The thymus is needed for NEONATAL TOLERANCE
T cells mature in the thymus but most die there.
Mouse
thymus
Constant
1-2 x 108
cells
5 x 107 per day
2 x 106 per day
98% of cells die in the thymus without inducing any inflammation or
any change in the size of the thymus.
Thymic macrophages phagocytose apoptotic thymocytes.
T cell development is marked by cell surface
molecule changes
As T cells mature in the thymus they change their expression of TcRassociated molecules and co-receptors.
These changes can be used as markers of their stage of maturation
Double
negative
Large
double
positive
Small
double
positive
Single
positive
CD3/TcRCD4-, 8-
CD3+
TcR-chain +
pre-TcR+ (pT
CD4+, 8+
CD3+
TcR +
CD4+
CD8+
CD3+
TcR +
CD4+

TcR+
CD3+
CD4-, 8-
Single
positive
98%
CD3+
TcR +
CD8+
Different developmental stages of thymocytes are
present in different parts of the thymus
Cortex
DN
DN
DN
CD25CD44+
CD25+
CD44+
CD25+, CD44low
DP
DP
DN
CD3+ pT:
CD3+ TcR+ CD3+ pT: CD25-, CD44-
SP
CD3+ TcR+
CD4+
SP
CD3+ TcR+
CD8+
Immature
double
negative &
positive
thymocytes
Medulla
Mature
single
positive
thymocytes
TcR rearrangement
CD25CD44+
DN
V
CD25+
CD44+
J
C
Germline configuration
DN
V
CD25+,
CD44low
D
DJ
C
V DJ
C
DN
D-J fusion
V-DJ fusion
C region spliced to VDJ fusion and -chain protein produced in cytoplasm
No TcR at cell surface
Similarities in the development of T and B cells:
A B cell reminder
Large
Pre-B
Surrogate light chain is transiently
expressed when VHDHJH CHm is
productively rearranged
1. Triggers entry into cell cycle
Expands pre-B cells with in
frame VDJ joins
2. Suppresses further H chain
rearrangement
Allelic exclusion
Similarities in the development of T and B cells:
Pre T cell  receptor
preTcR
-chain
DN
TcR
-chain
CD3+ very low
pT:
CD25- CD44-
CD4 CD8 preTcR
-chain
DP
TcR
-chain
CD3+ low
pT:
CD25- CD44CD4+ CD8+
1. Cell proliferates rapidly to yield daughter cells with the same  chain
Expands only cells with in-frame TcR  chains
2. Successful  rearrangement shuts off  rearrangement on 2nd chromosome
Ensures only one specificity of TcR expressed per cell
TcR rearrangement
DP
CD3+ low
pT:
CD25- CD44CD4+ CD8+
V
When proliferation stops,
the  chain starts to rearrange
J
C
Germline TcR 
V-J rearranged
TcR  1° transcript
Spliced TcR mRNA
DP
CD3+ TcR+
T cells can now recognise antigens
and interact with MHC class I & II
through CD4 & CD8
Selection can now begin
Mouse
thymus
5 x 107 per day
2 x 106 per day
How does the thymus choose which of
the cells entering the thymus are useful,
harmful and useless
Sorting the useful from the harmful and the
useless
Positive selection
Retention of thymocytes expressing TcR that are
RESTRICTED in their recognition of antigen by self MHC
i.e. selection of the USEFUL
Negative selection
Removal of thymocytes expressing TcR that either
recognise self antigens presented by self MHC or that
have no affinity for self MHC
i.e. selection of the HARMFUL and the USELESS
MHC restriction
Antigen can be seen
by the TcR only in the
context of an MHC
molecule
TcR will not bind to an
MHC molecule unless
there is an antigen in
the groove
In the presence of
antigen, the TcR must
have some affinity for
the MHC molecule
Experimental evidence for MHC restriction as a
marker of positive selection
CHIMERA
Thymus defect
Orange strain cells in a blue strain mouse
Which MHC haplotype will restrict the T cells,
Orange or blue?
Bone marrow transplant
Marrow defect
Transplant reconstitutes
marrow defective mouse
Studies in bone marrow chimeras show that
MHC restriction is learnt in the thymus
Bone marrow donor
MHC A
MHC (AxB)F1
MHC B
A
Irradated
bone marrow
recipients
A
MHC (AxB)F1
B
B
B
A
T cell
response
of recipient T
cells to antigen
MHC haplotype of APC
The MHC haplotype of the environment in which T cells
mature determines their MHC restriction element
Explanation of bone marrow chimera experiment:
Mice of a particular MHC haplotype only make T cells
restricted by that haplotype
MHC A
MHC B
MHC (AxB)F1
Able to make
T cells restricted
by MHC A
Able to make
T cells restricted
by MHC B
Able to make
T cells restricted
by MHC A or B
Bone marrow
must contain
potential to make T
cells restricted by
A and B MHC molecules
Explanation of bone marrow chimera experiment:
Irradiation prevents the bone marrow from
generating lymphocytes
MHC A
MHC B
Normal mice
MHC A
MHC B
Irradiation destroys the immune
system but has no effect on
the epithelial or dendritic cells of the
thymus
MHC A
MHC B
Mice now have an intact, functional thymic stroma
but have no thymocytes, T cells or bone marrow
These mice are severely immunodeficient and can only be
reconstituted by a bone marrow transplant
Explanation of bone marrow chimera experiment:
Reconstitution of irradiated mice with (AxB)F1 bone marrow
MHC (AxB)F1
Bone marrow contains the
potential to make T
cells restricted by
A and B MHC molecules
Transplant bone marrow
to reconstitute immune system
of immunodeficient mice
Irradiated
bone marrow
recipients
MHC A
MHC (AxB)F1
MHC B
Explanation of bone marrow chimera experiment:
MHC restriction is learnt in the thymus by positive selection
A x B T cell
precursors
Mouse with an MHC A
thymus, but A x B
bone marrow
MHC A Thymus
A x B T cell
precursors
Mouse with an MHC B
thymus, but A x B
bone marrow
MHC B Thymus
Mature T cells
restricted only
by MHC A
Mature T cells
restricted only
by MHC B
Explanation of bone marrow chimera experiment:
Peripheral T cells are restricted by the MHC type of the
thymus that they mature in
Bone marrow donor
MHC (AxB)F1
Bone marrow
recipients
MHC A
MHC B
B
A
B
A
T cell
response
of recipient T
cells to antigen
MHC haplotype of antigen presenting cells
Summary
Bone marrow chimeras show that
MHC restriction is learnt in the thymus
T cells are ‘educated’ in the thymus
to recognise antigens only in the context
of self MHC
MHC restriction is learnt in the
thymus by positive selection
The MHC haplotype of the environment in which T cells
mature determines their MHC restriction element
Negative Selection
Removal of thymocytes expressing TcR that either
recognise self antigens presented by self MHC or that
have no affinity for self MHC
i.e. selection of the HARMFUL and the USELESS
Superantigens can be used to probe the mechanisms of
negative selection
Nominal antigens & superantigens
Nominal antigens
Superantigens
Require processing to peptides
Not processed
TcR and  chains are involved
in recognition
Only TcR  chain involved
in recognition
>1 in 105 T cells recognise
each peptide
2-20% of T cells recognise
each superantigen
Recognition restricted by an
MHC class I or II molecule
Presented by almost any
MHC class II molecule
Almost all proteins can be
nominal antigens
Very few antigens are
superantigens
Suggests a strikingly different mechanism
of antigen presentation & recognition.
Superantigens
T cell
e.g. Staphylococcal
enterotoxins
Toxic shock syndrome toxin I
(TSST-1)
Staphylococcal enterotoxins
SEA, SEB, SEC, SED & SEE
Do not induce adaptive
responses, but trigger a
massive burst of cytokines that
may cause fever, systemic
toxicity & immune suppression
Severe food poisoning Toxic
shock syndrome
V
V TcR from
MHC A
haplotype
Class II from
MHC A to Z
haplotypes
APC
Interaction of SEB with MHC Class II
molecules and the TcR
MHC class II
TcR beta chain
MHC class II
SEB
TcR beta chain
SEB
Exogenous superantigen-V relationship
Superantigen
Human V region
SEA
1.1, 5.3, 6.3, 6.4
6.9, 7.3, 7.4, 9.1
3, 12, 14, 15, 17, 20
12
12, 13.1, 13.2
5, 12
5.1, 6.3, 6.4, 6.9, 8.1
2
SEB
SEC1
SEC2
SED
SEE
TSST-1
Explains why superantigens stimulate so many T cells
Effect of TSST-1 on T cells expressing V2
Cell number
Fresh PBMC unstained
PBMC cultured with TSST-1
Stained with anti-V3
Cell number
PBMC cultured with TSST-1
Stained with anti-V2
Fresh PBMC stained
with anti-V2
Fluorescence intensity
(i.e. amount of staining with anti-V antibody)
Other exogenous superantigens
Bacterial exoproteins
Staphylococcal exfoliative toxins
Streptococcus pyogenes erythrogenic toxins A & C
(?Streptococcal M protein?)
Yersinia enterocolitica superantigen
Clostridium perfingens superantigen
Mycoplasma arthritidis mitogen
T cell
Superantigens
Mouse mammary tumour
viruses (Mtv)
V
Vb
V TcR from
MHC A
haplotype
Cell-tethered superantigen
encoded by the viral genome
Class II from
MHC A to Z
haplotypes
APC
Endogenous superantigens
Mouse mammary tumour viruses (MMTV)
Retroviruses that contain an open reading frame
in a 3’ long terminal repeat that encodes a superantigen
associated with the cell surface of APC
Most mice carry 2-8 integrated MMTV proviruses in their genome
Integrated MMTV
Mtv-1, 2, 3, 6, 7 (Mls-1a), 8, 9, 11, 13 & 43
Infectious and transmitted by
milk
MMTV (C3H)
MMTV (SW)
MMTV (GR)
Endogenous superantigen V-relationship
Mtv
Mtv 8
Mtv 11
Mtv 9
Mtv 6
Mtv 1
Mtv 3
Mtv 13
Mtv 7
MMTV SW
MMTV C3H
MMTV GR
Murine V region
11
11
5.1, 5.2, 11
3, 5.1, 5.2
3
3
3
6, 7, 8.1, 9
6, 7, 8.1, 9
14
14
Stimulate T cells in a similar manner to exogenous supernatigens
Valuable tools in analysis of self tolerance
Mtv act in a similar manner to exogenous
superantigens in vitro
STIMULATOR CELLS
Mtv-7 +ve
RESPONDING T CELLS
Mtv-7 -ve
Irradiated
T
APC
Mtv-7 superantigen
T
T
T
T
T T
T
Only T cells with TcR containing V6, V8.1 and V9 proliferate
Mtv-7 interacts with V 6, V8.1 and V9 and activates
only cells bearing those TcR
Selective expansion of cells bearing certain V chains
How do pathogens use superantigens?
Unfocussed adaptive immune response activates cells of all
specificities as well as those specific for the superantigens
•
Reduces the possibility that effective T cell clonal selection
can eliminate the pathogen
•
Upon resolution, cells activated by the superantigen die,
leaving the host immunosuppressed
Transmission of infection
Transmission of infection
T
1. MMTV infected,
MHC class II
positive B cells
2. Massive T cell
response to MMTV superantigen
3. Vigorous T cell help
leads to B cell proliferation
and differentiation to longlived B cells
B
4. Infected cells traffic
to mammary gland
and infect young via
milk
Analysis of negative selection in vivo.
Mtv
Mtv-7 superantigen negative
Immature CD4+8+ thymocytes
expressing VV8.1 and V9
in the thymus
Negative selection
Mature CD4+ or CD8+
VV8.1 and V9
T cells in periphery
T
H
Y
M
U
S
Mtv-7 superantigen positive
Mtv-7 superantigen binds to V6,
V8.1 and V9+ve thymocytes
Immature CD4+8+ thymocytes
expressing VV8.1 and V9
in the thymus
Negative selection
No mature CD4+ or CD8+
PERIPHERY VV8.1 and V9
T cells in periphery
Analysis of negative selection in vivo.
Milk transmissible superantigens - MMTV
(C3H)
V14 present?
Male or female B10.BR
Yes
Male or female C3H
No
X
Female B10.BR
Male C3H
V14 present?
F1 offspring
Yes
X
Female C3H
F1 offspring
Male B10.BR
V14 present?
No
Deletion of V14 T cells in mice
infected with MMTV by milk
V14 present in
fostered pups?
+
Young male or
female C3H
Foster
female
B10.BR
+
Young male or
female C3H
Or B10.BR
Yes
No
Foster
female
C3H
MMTV transmitted to fostered pups by infected B cells found in milk
Are the signals that induce positive &
negative selection the same, or different?
SAME
specificity
T
H
Y
M
U
S
Immature thymocytes
Positive selection
Negative selection
Peripheral T cells
DIFFERENT
specificity
X
Hypotheses of self-tolerance
Avidity hypothesis
Affinity of the interaction between TcR & MHC
Density of the MHC:peptide complex on the cell surface
Quantitative difference in signal to thymocyte.
Differential signalling hypothesis
Type of signal that the TcR delivers to the cell
Qualitative difference in signal to thymocyte.
Removal of useless cells
Peptide is not recognised or irrelevant
Thymocyte receives no signal, fails to be positively selected
and dies by apoptosis.
WEAK OR NO SIGNAL
T cell
TcR
CD8
 
MHC
Class I
Thymic epithelial cell
Positive selection
Peptide is a partial agonist
Thymocyte receives a partial signal and is rescued from apoptosis
i.e. the cell is positively selected to survive and mature.
PARTIAL SIGNAL
T cell
TcR
CD8
 
MHC
Class I
Thymic epithelial cell
Negative selection
Peptide is an agonist
Thymocyte receives a powerful signal and undergoes apoptosis
i.e. the cell is negatively selected and dies.
FULL SIGNAL
T cell
TcR
CD8
 
CD8
MHC
Class I
 
Thymic epithelial cell
The thymus accepts T cells that fall into a narrow
window of affinity for MHC molecules
Useless
Neglect
Useful
Harmful
Positively select Negatively select
Number
of cells
Low
High
Affinity of TcR/MHC interaction
Positive & negative selection occurs in distinct
thymic microenvironments
Cortex
Proliferation
CD3Positive selection
CD3+ TcR+
Negative selection
DN
DP
Cortical
epithelial
cells
DP
Medulla
CD3+ TcR+
SP
CD3+ TcR+
CD8+ or CD4+
Immature
double
negative &
positive
thymocytes
Dendritic
cells medullary
Epithelial cells &
Macrophages
Mature
single
positive
thymocytes
How accurate are these models of
positive and negative selection?
Positive selection:
Relied on very complex chimera experiments
Relied on proof of MHC restriction as an outcome which is tested in an
‘unnatural’ response using MHC mismatched presenting cells
Negative selection:
Relied on exceptionally powerful superantigens operating outside the
normal mechanisms of antigen recognition
Illustration of selection using TcR transgenic mice
Generation of transgenic mice
T
T cell clone with known
TcR specificity and MHC restriction
Rearranged  chain
cDNA construct
Rearranged  chain
cDNA construct
Re-implant
}
Analyse offspring
for transgene
expression.
Inject into fertilised
mouse ovum
In TcR transgene-expressing mice almost all thymocytes express the
transgenic TcR due to ALLELIC EXCLUSION.
Cells that fail positive selection die in the thymus (neglect)
In TcR transgenic mice expressing an MHC A restricted TcR, all
thymocytes express the MHC A restricted TcR
DN
MHC B
DP
Transgenically express
MHC A restricted TcR in
an MHC B mouse
CD3-
CD3+ TcR+
SP
No single +ve cells are
present in the periphery
CD3+ TcR+
CD8+ or CD4+
Thymocytes die at the double positive stage after failing +ve selection
due to a lack of MHC A
Positive selection determines the restriction element of
the TcR AND the expression of CD4 or CD8
TcR transgenic mouse
TcR transgenic mouse
TcR from MHC class Irestricted T cell
TcR from MHC class IIrestricted T cell
Only CD8
cells mature
Only CD4
cells mature
Restriction element and co-receptor expression are co-ordinated
Instructive model: Signal from CD4 silences the CD8 expression & vice
versa?
Stochastic/selection model: Cells randomly inactivate CD4 or CD8 gene,
then test for matching of TcR restriction with co-receptor expression?
Double positive to single positive transition
Single CD4+ thymocyte
Double positive thymocyte
-ve
TcR
TcR
3
CD4
2

MHC Class I
TcR
√
X
CD8
TcR
3
CD8
CD4
2

MHC Class II
MHC Class I
MHC Class II
Thymic epithelial cell
Instructive model: Signal from CD4 silences the CD8 expression &
vice versa
Double positive to single positive transition
Single CD4+ thymocyte
Double positive thymocyte
TcR
TcR
3
CD4
2

MHC Class I
TcR
√
X
CD8
TcR
3
CD8
CD4
2

MHC Class II
MHC Class I
MHC Class II
Thymic epithelial cell
Stochastic/selection model: Cells randomly inactivate CD4 or CD8 gene,
whilst testing a match of TcR restriction
Deletion of cells in the thymus:
differential effect on the mature and immature repertoire
TcR transgenic mouse
TcR from T cell specific for hen egg lysosyme (HEL)
~100% of T cells/thymocytes express anti-HEL TcR
Immunise
with HEL
Analyse peripheral
Analyse thymus:
T cells:
All transgenic T cells die
All transgenic T cells
by apoptosis
proliferate
Thymocytes activated by antigen in the thymic environment die
T cells activated by antigen in the periphery proliferate
How can the thymus express all self antigens
– including self antigens only made by
specialised tissues?
How do we become self tolerant to these
antigens?
Nature Immunology
November 2001
Promiscuous expression of tissue-specific genes
by medullary thymic epithelial cells
How is self tolerance established to antigens that
can not be expressed in the thymus?
•
T cells bearing TcR reactive with proteins expressed in the thymus
are deleted.
•
Some self proteins are not expressed in the thymus e.g. antigens
first expressed at puberty
•
Self tolerance can be induced outside the thymus
PERIPHERAL TOLERANCE or ANERGY
A state of immunological inactivity caused by a failure to deliver
appropriate signals to T or B cells when stimulated with antigen
i.e. a failure of antigen presenting cells to deliver COSTIMULATION
T helper cells costimulate B cells
Two - signal models of activation
Signal 1 antigen & antigen
receptor
B
Y
CD40
ACTIVATION
Th
Signal 2 - T cell help
T cell antigen receptor
Co-receptor (CD4)
MHC class II
and peptide
CD40 Ligand (CD154)
Antigen presentation - T cells are co-stimulated
Signal 1 antigen & antigen
receptor
Th
APC
ACTIVATION
Signal 2
B7 family members (CD80 & CD86)
CD28
Costimulatory molecules are expressed by most APC including dendritic cells,
monocytes, macrophages, B cells etc., but not by cells that have no
immunoregulatory functions such as muscle, nerves, hepatocytes, epithelial cells etc.
Mechanism of co-stimulation in T cells
Low affinity IL-2
receptor
Antigen
1
IL-2
IL-2
IL-2R
IL-2R
Resting T cells
Express IL-2 receptor and  chains but no
 chain or IL-2
Signal 1
NFAT binds to the promoter of of the
 chain gene of the IL-2 receptor.
The  chain converts the IL-2R
to a high affinity form
Mechanism of co-stimulation in T cells
Costimulation
Antigen
Signal 2
1
2
Activates AP-1 and NFk-B to increase IL2 gene transcription by 3 fold
Stabilises and increases the half-life of IL2 mRNA by 20-30 fold
IL-2
IL-2R
IL-2 production increased by 100 fold
overall
Immunosuppressive drugs illustrate the importance of IL-2 in immune responses
Cyclosporin & FK506 inhibit IL-2 by disrupting TcR signalling
Rapamycin inhibits IL-2R signalling
Anergy
Antigen
Naïve
T cell
1
Signal 1
only
IL-2
IL-2R
Epithelial
cell
Self peptide epitopes presented
by a non-classical APC e.g. an
epithelial cell
The T cell is unable to produce IL-2 and
therefore is unable to proliferate or be
clonally selected.
Unlike immunosupressive drugs that
inhibit ALL specificities of T cell, signal 1
in the absence of signal 2 causes antigen
specificT cell unresponsiveness.
Arming of effector T cells
Clonal selection and differentiation
APC
T
Activation of NAÏVE T cells by signal 1
and 2 is not sufficient to trigger
effector function, but…..
the T cell will be activated to proliferate
and differentiate under the control of
autocrine IL-2 to an effector T cell.
These T cells are ARMED
IL-2
Effector
T cell
How can this cell give help
to, or kill cells, that express
low levels of B7 family
costimulators?
Effector function or Anergy?
Clonally selected,
proliferating and
differentiated
T cell i.e. ARMED sees
antigen on
a B7 -ve epithelial cell
IL-2
Armed
Effector
T cell
The effector programme
of the T cell is activated
without costimulation
Armed
Effector
T cell
This contrasts the
situation with naïve T
cells, which are
anergised without
costimulation
Naïve
T cell
CD28
TcR
Co-receptor
Kill
Epithelial
cell
Epithelial
cell
Epithelial
cell
Costimulatory molecules also associate
with inhibitory receptors
T cell
Signal 1 +
2
2
Activated T cell
-- -- CD28lo CTLA-4hi
CD28
B7
B7
CD28 cross linked by B7
Co-stimulation
induces CTLA-4
Cross-linking of CTLA-4
by B7 inhibits co-stimulation
and inhibits T cell activation
CTLA-4 binds CD28 with a higher affinity than B7 molecules
The lack of signal 2 to the T cell shuts down the T cell response.
The danger hypothesis & co-stimulation
Full expression of T cell function and self tolerance
depends upon when and where co-stimulatory molecules are expressed.
Cell containing only
self antigens
No danger
Apoptotic cell death.
A natural, often useful
cell death.
No danger
APC
APC
Innocuous challenge to the immune system fails to activate APC and fails
to activate the immune system
Fuchs & Matzinger 1995
The danger hypothesis
Necrotic cell death
e.g. tissue damage,
virus infection etc
APC
DANGER
Pathogens recognised
by microbial patterns
APC
APC that detect ‘danger’ signals express costimulatory
molecules, activate T cells and the immune response
How the danger hypothesis suggests a review of
immunological dogma
• Antigens induce tolerance or immunity depending upon the ability of the
immune system to sense them as ‘dangererous’, and not by sensing whether
they are self or ‘non-self’.
• There is no window for tolerance induction in neonates - if a ‘danger signal’ is
received, the neonatal immune system will respond
• Neonatal T cells are not intrinsically tolerisable but the natural antiinflammatory nature of the neonatal environment predisposes to tolerance
• Apoptosis, the ‘non-dangerous’ death of self cells may prevent autoimmunity
when old or surplus cells are disposed of.
• Suggests that tolerance is the default pathway of the immune system on
encountering antigens.
• Explains why immunisations require adjuvants to stimulate cues of danger
such as cytokines or costimulatory molecule expression.
Doesn’t exclude self-nonself discrimination, but the danger hypothesis
will be very hard to disprove experimentally.