topic 7 t cell development, repertoire selection and immune self tolerance ©dr. colin r.a. hewitt...
TRANSCRIPT
Topic 7
T Cell Development, Repertoire Selection and Immune
Self Tolerance
©Dr. Colin R.A. Hewitt
Why is a mechanism for repertoire selectionand self tolerance needed?
TT
TT T
TTT
TT
T
T
TT
T
T T
T
TTT
T
TT
T
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:
2. Useless
T T T
APC
3. Useful
Foreignantigen
recognition
T
1. Harmful
Selfantigen
recognition
Self proteins enter the endogenous and exogenousantigen processing pathways
Self cellularproteins
Self serum& cellularproteins
Processing pathways do not distinguish self from non-self
>90% of eluted peptides are derived from self proteinsYet self antigens do not usually activate T cells
Self peptides load onto MHC class I & II molecules
Purify stable MHC-peptide complexes
Fractionate and microsequence
peptides
Acid elute peptides
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?
The immune system allows a limited degreeof self recognition
MHC Bhaplotype
APC
T cells are only allowed to develop if their TcR recognise parts of self MHC
MHC AhaplotypeT CELL
Explains why T cells of MHC haplotype A do not recognise antigen specific presented by MHC haplotype B
MHC Ahaplotype
APC
YT Y YT T
APC
Harmful Useless Useful
YT
?
Positivelyselect
Negativelyselect
Wholly self-reactive and useless T cells are removed MHC-restricted are retained
THYMUS
YT YTY YY YT T
Y YT T
Y Y YT T T Y Y
YYT
YT T T
Random TcRrepertoire
ensures diversity
YT YTYT
Neglect
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
Cortex
Medulla
Corticalepithelial cell
Medullaryepithelial cell
Dendritic cell
Thymocyte
Macrophage
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 No mature T cellsIn adult
Thymus intact Mature T cellsIn adult
Roles of the bone marrow and thymus in T cell maturation
Defective lymphocyteproduction
Normal thymusscid/scid
Thymus defectNormal bone
marrownu/nu
No mature T cellsIn adults
No mature T cellsIn adults
Thymus colonised by thymocytes from the thymus defective, i.e. orange, mouse
Thymus graft
Bone marrow transplant
Thymus colonised by thymocytes from thymus defective, i.e. orange, mouse
Marrow defect
Thymus defect
Bone marrow supplies T cells, and they mature in the thymus
The thymus matures T cells afterbirth, but early in life
Remove Thymus
Mature T & B cells
Adult Neonate
No T cellsMature B cells present
T cells not yet left thymus
The thymus is needed to generate mature T cells
The thymus is most active in the foetaland neonatal period
T cells vs. OVA
Adult Neonate
No T cells vs.OVA
OVA
The thymus is needed for NEONATAL TOLERANCE
KLH
T cells vs. KLH T cells vs. KLH
Mousethymus
5 x 107 per day
T cells mature in the thymus but most die there.
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.
2 x 106 per day
Constant1-2 x 108
cells
98%
T cell development is marked by cell surfacemolecule changes
As T cells mature in the thymus they change their expression of TcR-associated molecules and co-receptors.
These changes can be used as markers of their stage of maturation
CD3/TcR-CD4-, 8-
Doublenegative
CD3+TcR-chain +
pre-TcR+ (pTCD4+, 8+
Largedoublepositive
CD3+TcR +
CD4+CD8+
Smalldoublepositive
TcR+CD3+
CD4-, 8-
CD3+TcR +
CD4+
Singlepositive
CD3+TcR +
CD8+
Singlepositive
Different developmental stages of thymocytes arepresent in different parts of the thymus
CortexImmaturedoublenegative &positivethymocytes
MedullaMaturesinglepositivethymocytes
DP
CD3+ pT:
DN
CD3+ pT:CD25-, CD44-
DP
CD3+ TcR+
DN
CD25+CD44+
DN
CD25-CD44+
DN
CD25+, CD44low
SP
CD3+ TcR+CD8+
CD3+ TcR+CD4+
SP
TcR rearrangement
DNCD25+,CD44low
V D J C
Germline configuration
V DJ C
D-J fusion
DNCD25+CD44+
DNCD25-CD44+
C region spliced to VDJ fusion and -chain protein produced in cytoplasmNo TcR at cell surface
V DJ C
V-DJ fusion
Similarities in the development of T and B cells:A B cell reminder
Surrogate light chain is transiently expressed when VHDHJH CH is
productively rearranged
1. Triggers entry into cell cycleExpands pre-B cells with in frame VDJ joins
2. Suppresses further H chain rearrangementAllelic exclusion
LargePre-B
DN CD3+ very lowpT:
CD25- CD44-
1. Cell proliferates rapidly to yield daughter cells with the same chainExpands only cells with in-frame TcR chains
2. Successful rearrangement shuts off rearrangement on 2nd chromosomeEnsures only one specificity of TcR expressed per cell
Similarities in the development of T and B cells:Pre T cell receptor
TcR-chain
preTcR-chain
TcR-chain
preTcR-chain
CD8CD4
DPCD3+ low
pT:CD25- CD44-CD4+ CD8+
TcR rearrangement
Germline TcR
J CV
V-J rearrangedTcR 1° transcript
Spliced TcR mRNA
CD3+ TcR+
DPT cells can now recognise antigensand interact with MHC class I & II
through CD4 & CD8
Selection can now begin
When proliferation stops, the chain starts to rearrange
DPCD3+ low
pT:CD25- CD44-CD4+ CD8+
Mousethymus
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
Retention of thymocytes expressing TcR that are RESTRICTED in their recognition of antigen by self MHC
i.e. selection of the USEFUL
Positive selection
Negative selection
Removal of thymocytes expressing TcR that either recognise self antigens presented by self MHC or that
have no affinity for self MHCi.e. selection of the HARMFUL and the USELESS
Sorting the useful from 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
Bone marrow transplant
Transplant reconstitutesmarrow defective mouse
Thymus defect
Marrow defect
Experimental evidence for MHC restriction as a marker of positive selection
CHIMERAOrange strain cells in a blue strain mouse
Which MHC haplotype will restrict the T cells, Orange or blue?
Studies in bone marrow chimeras show thatMHC restriction is learnt in the thymus
T cellresponse
of recipient Tcells to antigen
MHC A
The MHC haplotype of the environment in which T cellsmature determines their MHC restriction element
MHC (AxB)F1
Bone marrow donor
MHC (AxB)F1
MHC haplotype of APC
A B A B A B
Irradatedbone marrow
recipients MHC B
MHC (AxB)F1
Able to makeT cells restrictedby MHC A or B
MHC A
Able to makeT cells restricted
by MHC A
MHC B
Able to makeT cells restricted
by MHC B
Explanation of bone marrow chimera experiment:
Mice of a particular MHC haplotype only make T cellsrestricted by that haplotype
Bone marrowmust contain
potential to make T cells restricted by
A and B MHC molecules
Irradiation destroys the immune system but has no effect on
the epithelial or dendritic cells of the thymus
MHC A MHC BMHC A MHC B
Normal mice
MHC A MHC BMice now have an intact, functional thymic stromabut have no thymocytes, T cells or bone marrow
Explanation of bone marrow chimera experiment:
Irradiation prevents the bone marrow fromgenerating lymphocytes
These mice are severely immunodeficient and can only bereconstituted by a bone marrow transplant
MHC (AxB)F1
Bone marrow contains thepotential to make T cells restricted by
A and B MHC molecules
MHC A MHC (AxB)F1 MHC B
Irradiatedbone marrow
recipients
Transplant bone marrowto reconstitute immune systemof immunodeficient mice
Explanation of bone marrow chimera experiment:
Reconstitution of irradiated mice with (AxB)F1 bone marrow
Mouse with an MHC Athymus, but A x B
bone marrow
Mature T cellsrestricted onlyby MHC A
Mouse with an MHC Bthymus, but A x B
bone marrow
Mature T cellsrestricted onlyby MHC B
A x B T cellprecursors
MHC A Thymus
A x B T cellprecursors
MHC B Thymus
Explanation of bone marrow chimera experiment:
MHC restriction is learnt in the thymus by positive selection
MHC (AxB)F1
Bone marrow donor
T cellresponse
of recipient Tcells to antigen
A B A B
MHC A MHC B
Bone marrowrecipients
MHC haplotype of antigen presenting cells
Explanation of bone marrow chimera experiment:
Peripheral T cells are restricted by the MHC type of thethymus that they mature in
T cells are ‘educated’ in the thymusto recognise antigens only in the context
of self MHC
The MHC haplotype of the environment in which T cellsmature determines their MHC restriction element
Bone marrow chimeras show thatMHC restriction is learnt in the thymus
Summary
MHC restriction is learnt in thethymus by positive selection
Removal of thymocytes expressing TcR that either recognise self antigens presented by self MHC or that
have no affinity for self MHCi.e. selection of the HARMFUL and the USELESS
Negative Selection
Superantigens can be used to probe the mechanisms of negative selection
Nominal antigens & superantigens
Nominal antigens
Require processing to peptides
TcR and chains are involved in recognition
>1 in 105 T cells recognise each peptide
Recognition restricted by an MHC class I or II molecule
Almost all proteins can be nominal antigens
Superantigens
Not processed
Only TcR chain involved in recognition
2-20% of T cells recognise each superantigen
Presented by almost any MHC class II molecule
Very few antigens are superantigens
Suggests a strikingly different mechanismof antigen presentation & recognition.
Superantigens
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
Class II fromMHC A to Zhaplotypes
TcR fromMHC Ahaplotype
T cell
APC
V V
Interaction of SEB with MHC Class II molecules and the TcR
MHC class IITcR beta chain
MHC class IISEB
TcR beta chainSEB
Exogenous superantigen-V relationship
Superantigen Human V region
SEA 1.1, 5.3, 6.3, 6.46.9, 7.3, 7.4, 9.1
SEB 3, 12, 14, 15, 17, 20SEC1 12SEC2 12, 13.1, 13.2SED 5, 12SEE 5.1, 6.3, 6.4, 6.9, 8.1TSST-1 2
Explains why superantigens stimulate so many T cells
Fresh PBMC stainedwith anti-V2
PBMC cultured with TSST-1Stained with anti-V3
Fresh PBMC unstained
Fluorescence intensity(i.e. amount of staining with anti-V antibody)
Cel
l n
um
ber
Effect of TSST-1 on T cells expressing V2
PBMC cultured with TSST-1Stained with anti-V2
Cel
l n
um
ber
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
TcR fromMHC Ahaplotype
T cell
APC
Class II fromMHC A to Zhaplotypes
VbV V
Superantigens
Mouse mammary tumour viruses (Mtv)
Cell-tethered superantigen encoded by the viral genome
Endogenous superantigens
Mouse mammary tumour viruses (MMTV)Retroviruses that contain an open reading frame
in a 3’ long terminal repeat that encodes a superantigenassociated 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)
Mtv Murine V regionMtv 8 11Mtv 11 11Mtv 9 5.1, 5.2, 11Mtv 6 3, 5.1, 5.2Mtv 1 3Mtv 3 3Mtv 13 3Mtv 7 6, 7, 8.1, 9MMTV SW 6, 7, 8.1, 9MMTV C3H 14MMTV GR 14
Endogenous superantigen V-relationship
Stimulate T cells in a similar manner to exogenous supernatigensValuable tools in analysis of self tolerance
Irradiated
Mtv-7 superantigen
APC T
Only T cells with TcR containing V6, V8.1 and V9 proliferateMtv-7 interacts with V 6, V8.1 and V9 and activates
only cells bearing those TcRSelective expansion of cells bearing certain V chains
Mtv act in a similar manner to exogenous superantigens in vitro
T
TT
T
TT
T
STIMULATOR CELLSMtv-7 +ve
RESPONDING T CELLSMtv-7 -ve
How do pathogens use 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
Unfocussed adaptive immune response activates cells of all specificities as well as those specific for the superantigens
Transmission of infection
B1. MMTV infected,
MHC class IIpositive B cells
Transmission of infection
T2. Massive T cellresponse to MMTV superantigen
3. Vigorous T cell help leads to B cell proliferation and differentiation to long-lived B cells
4. Infected cells traffic to mammary gland and infect young via milk
Analysis of negative selection in vivo.Mtv
Mtv-7 superantigen binds to V6, V8.1 and V9+ve thymocytes
Mtv-7 superantigen positive
Negative selection
Immature CD4+8+ thymocytesexpressing VV8.1 and V9
in the thymus
No mature CD4+ or CD8+VV8.1 and V9T cells in periphery
Mtv-7 superantigen negative
Immature CD4+8+ thymocytesexpressing VV8.1 and V9
in the thymus
Negative selection
Mature CD4+ or CD8+VV8.1 and V9T cells in periphery
THYMUS
PERIPHERY
Analysis of negative selection in vivo.Milk transmissible superantigens - MMTV (C3H)
Male or female B10.BR
Male or female C3H
V14 present?
Yes
No
X
Male C3HFemale B10.BR
No
V14 present?
F1 offspring
Male B10.BRFemale C3H
X
V14 present?
F1 offspring
Yes
No
Deletion of V14 T cells in miceinfected with MMTV by milk
+Fosterfemale
B10.BR
Young male orfemale C3H
Yes
V14 present infostered pups?
+Fosterfemale C3H
Young male orfemale C3HOr B10.BR
MMTV transmitted to fostered pups by infected B cells found in milk
THYMUS
Are the signals that induce positive & negative selection the same, or different?
Negative selection
Peripheral T cells
SAMEspecificity
DIFFERENTspecificity
Positive selection
Immature thymocytes
X
Hypotheses of self-tolerance
Avidity hypothesis
Affinity of the interaction between TcR & MHCDensity 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 cellsPeptide is not recognised or irrelevant
Thymocyte receives no signal, fails to be positively selectedand dies by apoptosis.
WEAK OR NO SIGNAL
CD8
TcR
T cell
Thymic epithelial cell
MHCClass I
Thymic epithelial cell
MHCClass I
Positive selectionPeptide is a partial agonist
Thymocyte receives a partial signal and is rescued from apoptosisi.e. the cell is positively selected to survive and mature.
PARTIAL SIGNAL
CD8
TcR
T cell
Thymic epithelial cell
MHCClass I
Negative selectionPeptide is an agonist
Thymocyte receives a powerful signal and undergoes apoptosisi.e. the cell is negatively selected and dies.
FULL SIGNAL
CD8
CD8
TcR
T cell
The thymus accepts T cells that fall into a narrow window of affinity for MHC molecules
Numberof cells
Affinity of TcR/MHC interactionLow High
UselessNeglect
UsefulPositively select
HarmfulNegatively select
CortexImmaturedoublenegative &positivethymocytes
MedullaMaturesinglepositivethymocytes
Positive & negative selection occurs in distinct thymic microenvironments
SP
CD3+ TcR+CD8+ or CD4+
Corticalepithelialcells
DNProliferationCD3-
DPPositive selection
CD3+ TcR+
DPNegative selection
CD3+ TcR+
Dendriticcells medullary Epithelial cells &Macrophages
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 miceGeneration of transgenic mice
TT cell clone with known
TcR specificity and MHC restriction
Rearranged chaincDNA construct
Rearranged chaincDNA construct
}Inject into fertilised
mouse ovum
Re-implant
Analyse offspringfor transgeneexpression.
In TcR transgene-expressing mice almost all thymocytes express thetransgenic TcR due to ALLELIC EXCLUSION.
Cells that fail positive selection die in the thymus (neglect)
Thymocytes die at the double positive stage after failing +ve selection due to a lack of MHC A
DP
CD3+ TcR+
No single +ve cells arepresent in the periphery
SP
CD3+ TcR+CD8+ or CD4+
DN
CD3-
MHC B
In TcR transgenic mice expressing an MHC A restricted TcR, all thymocytes express the MHC A restricted TcR
Transgenically express MHC A restricted TcR in an MHC B mouse
Positive selection determines the restriction element of the TcR AND the expression of CD4 or CD8
TcR transgenic mouse
TcR from MHC class I-restricted T cell
TcR transgenic mouse
TcR from MHC class II-restricted T cell
Only CD8cells mature
Only CD4cells 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?
Instructive model: Signal from CD4 silences the CD8 expression & vice versa
CD8
MHC Class I MHC Class II
3 2
TcR TcR
CD4
Double positive thymocyte
Thymic epithelial cell
MHC Class II
2
TcR
CD4
MHC Class I
3
TcR-ve
CD8
Double positive to single positive transition
Single CD4+ thymocyte
X √
MHC Class II
2
TcR
MHC Class I
3
TcR
Stochastic/selection model: Cells randomly inactivate CD4 or CD8 gene, whilst testing a match of TcR restriction
CD8
MHC Class I MHC Class II
3 2
TcR TcR
CD4
Double positive thymocyte
Thymic epithelial cell
CD4
CD8
Single CD4+ thymocyte
CD4
CD8 CD4
Double positive to single positive transition
X √
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
Immunisewith HEL
Analyse peripheralT cells:
All transgenic T cells proliferate
Analyse thymus:All transgenic T cells die
by apoptosis
Thymocytes activated by antigen in the thymic environment dieT 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 ImmunologyNovember 2001
Promiscuous expression of tissue-specific genes by medullary thymic epithelial cells
How is self tolerance established to antigens thatcan 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 cellsTwo - signal models of activation
YYYB
T cell antigen receptor
Co-receptor (CD4)
CD40 Ligand (CD154)
Th
Signal 2 - T cell help
CD40
MHC class IIand peptide
Signal 1 antigen & antigenreceptor
ACTIVATION
Antigen presentation - T cells are co-stimulated
APC Th
Signal 1 antigen & antigenreceptor
Signal 2
B7 family members (CD80 & CD86) CD28
ACTIVATION
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.
IL-2
IL-2R
Express IL-2 receptor- and chains but no
chain or IL-2
Mechanism of co-stimulation in T cells
Signal 1
NFAT binds to the promoter of of the chain gene of the IL-2 receptor.
The chain converts the IL-2Rto a high affinity form
IL-2
IL-2R
1
Antigen
Resting T cells
Low affinity IL-2 receptor
IL-2
IL-2R
1
Antigen
2
Costimulation
Signal 2Activates AP-1 and NF-B to increase IL-2 gene transcription by 3 fold
Stabilises and increases the half-life of IL-2 mRNA by 20-30 fold
IL-2 production increased by 100 fold overall
Mechanism of co-stimulation in T cells
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
IL-2
IL-2R
1
Antigen
Epithelialcell
NaïveT cell
Signal 1only
Anergy
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.
Self peptide epitopes presentedby a non-classical APC e.g. an
epithelial cell
Arming of effector T cells
APC T
Activation of NAÏVE T cells by signal 1 and 2 is not sufficient to trigger
effector function, but…..
IL-2EffectorT cell
Clonal selection and differentiation
How can this cell give help to, or kill cells, that express
low levels of B7 family costimulators?
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
ArmedEffectorT cell
CD28
Co-receptor
TcR
IL-2
Epithelialcell
NaïveT cell
Epithelialcell
Clonally selected,proliferating and
differentiatedT cell i.e. ARMED sees
antigen ona B7 -ve epithelial cell
Epithelialcell
ArmedEffectorT cell
Kill
The effector programmeof the T cell is activatedwithout costimulation
This contrasts the situation with naïve T
cells, which are anergised without
costimulation
Effector function or Anergy?
CD28lo
Activated T cell
CD28 cross linked by B7
Costimulatory molecules also associatewith inhibitory receptors
CTLA-4 binds CD28 with a higher affinity than B7 molecules
CTLA-4hi
B7
CD28
T cell
B7
2 2Signal 1 +
Co-stimulationinduces CTLA-4
The lack of signal 2 to the T cell shuts down the T cell response.
Cross-linking of CTLA-4by B7 inhibits co-stimulationand inhibits T cell activation
- - -- -
The danger hypothesis & co-stimulation
Fuchs & Matzinger 1995
Full expression of T cell function and self tolerance depends upon when and where co-stimulatory molecules are expressed.
Apoptotic cell death.A natural, often usefulcell death.
APC
APC
No danger
No dangerCell containing onlyself antigens
Innocuous challenge to the immune system fails to activate APC and failsto activate the immune system
The danger hypothesis
APC
APC
Necrotic cell deathe.g. tissue damage,virus infection etc
Pathogens recognisedby microbial patterns
DANGER
APC that detect ‘danger’ signals express costimulatorymolecules, activate T cells and the immune response
• 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 anti-inflammatory 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.
How the danger hypothesis suggests a review of immunological dogma
Doesn’t exclude self-nonself discrimination, but the danger hypothesis will be very hard to disprove experimentally.