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T Cell Development, Repertoire Selection and Immune

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1 T Cell Development, Repertoire Selection and Immune
Topic 7 T Cell Development, Repertoire Selection and Immune Self Tolerance ©Dr. Colin R.A. Hewitt

2 Why is a mechanism for repertoire selection and self tolerance needed?
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: T 1. Harmful Self antigen recognition 2. Useless T T APC 3. Useful Foreign antigen recognition

3 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

4 Self peptides load onto MHC class I & II molecules
Purify stable MHC-peptide 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

5 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?

6 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 B haplotype APC MHC A haplotype APC

7 Wholly self-reactive and useless T cells are removed MHC-restricted are retained
Random TcR repertoire ensures diversity THYMUS Y T Y T ? Y T APC Harmful Useless Useful Negatively select Positively select Neglect

8 Stroma provides a microenvironment for T cell development & selection
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 Medulla Cortical epithelial cell Dendritic cell Macrophage Medullary epithelial cell

9 The thymus is required for T cell maturation
Athymic mice (nude) and humans (DiGeorge syndrome) are immunodeficient due to a lack of T cells No mature T cells In adult Neonatal thymectomy Mature T cells In adult Thymus intact

10 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

11 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

12 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

13 The thymus is most active in the foetal
and neonatal period OVA Adult Neonate KLH T cells vs. OVA No T cells vs.OVA T cells vs. KLH The thymus is needed for NEONATAL TOLERANCE

14 T cells mature in the thymus but most die there.
Mouse thymus 5 x 107 per day Constant 1-2 x 108 cells 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.

15 T cell development is marked by cell surface
molecule 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 98% CD3/TcR- CD4-, 8- Double negative CD3+ TcR-chain + pre-TcR+ (pT CD4+, 8+ Large double positive CD3+ TcR + CD4+ CD8+ Small double positive CD3+ TcR + CD4+ Single positive TcR+ CD3+ CD4-, 8-  CD3+ TcR + CD8+ Single positive

16 Different developmental stages of thymocytes are
present in different parts of the thymus Cortex Immature double negative & positive thymocytes Medulla Mature single DN CD25- CD44+ DN CD25+ CD44+ DN CD25+, CD44low DN CD3+ pT: CD25-, CD44- DP CD3+ pT: DP CD3+ TcR+ SP CD3+ TcR+ CD8+ CD4+

17 Germline configuration
TcR rearrangement DN CD25+ CD44+ CD25- V D J C Germline configuration V D J C D-J fusion V D J C V-DJ fusion DN CD25+, CD44low C region spliced to VDJ fusion and -chain protein produced in cytoplasm No TcR at cell surface

18 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 Triggers entry into cell cycle Expands pre-B cells with in frame VDJ joins 2. Suppresses further H chain rearrangement Allelic exclusion

19 Similarities in the development of T and B cells:
Pre T cell a receptor preTcR a-chain TcR b-chain CD8 CD4 TcR b-chain preTcR a-chain DN CD3+ very low pT: CD25- CD44- DP CD3+ low pT: CD25- CD44- CD4+ CD8+ 1. Cell proliferates rapidly to yield daughter cells with the same  chain Expands only cells with in-frame TcR b chains 2. Successful  rearrangement shuts off  rearrangement on 2nd chromosome Ensures only one specificity of TcR expressed per cell

20 TcR rearrangement DP DP Selection can now begin
CD3+ low pT: CD25- CD44- CD4+ CD8+ When proliferation stops, the  chain starts to rearrange Germline TcR  J C V V-J rearranged TcR  1° transcript Spliced TcR mRNA CD3+ TcR+ DP T cells can now recognise antigens and interact with MHC class I & II through CD4 & CD8 Selection can now begin

21 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

22 Sorting the useful from the harmful and the useless
Positive selection Negative selection Retention of thymocytes expressing TcR that are RESTRICTED in their recognition of antigen by self MHC i.e. selection of the USEFUL 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

23 Antigen can be seen by the TcR only in the context of an MHC molecule
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

24 Experimental evidence for MHC restriction as a marker of positive selection
CHIMERA Orange strain cells in a blue strain mouse Which MHC haplotype will restrict the T cells, Orange or blue? Thymus defect Bone marrow transplant Transplant reconstitutes marrow defective mouse Marrow defect

25 Studies in bone marrow chimeras show that
MHC restriction is learnt in the thymus MHC (AxB)F1 Bone marrow donor Irradated bone marrow recipients MHC A MHC (AxB)F1 MHC B MHC haplotype of APC A B T cell response of recipient T cells to antigen The MHC haplotype of the environment in which T cells mature determines their MHC restriction element

26 Mice of a particular MHC haplotype only make T cells
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

27 Irradiation prevents the bone marrow from generating lymphocytes
Explanation of bone marrow chimera experiment: Irradiation prevents the bone marrow from generating lymphocytes Irradiation destroys the immune system but has no effect on the epithelial or dendritic cells of the thymus MHC A MHC B MHC A MHC B Normal mice 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

28 Reconstitution of irradiated mice with (AxB)F1 bone marrow
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 MHC A MHC (AxB)F1 MHC B Irradiated bone marrow recipients

29 MHC restriction is learnt in the thymus by positive selection
Explanation of bone marrow chimera experiment: MHC restriction is learnt in the thymus by positive selection A x B T cell precursors MHC A Thymus Mature T cells restricted only by MHC A Mouse with an MHC A thymus, but A x B bone marrow A x B T cell precursors MHC B Thymus Mature T cells restricted only by MHC B Mouse with an MHC B thymus, but A x B bone marrow

30 Peripheral T cells are restricted by the MHC type of the
Explanation of bone marrow chimera experiment: Peripheral T cells are restricted by the MHC type of the thymus that they mature in MHC (AxB)F1 Bone marrow donor MHC A MHC B Bone marrow recipients T cell response of recipient T cells to antigen A B MHC haplotype of antigen presenting cells

31 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

32 i.e. selection of the HARMFUL and the USELESS
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

33 Nominal antigens & superantigens
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 mechanism of antigen presentation & recognition.

34 Superantigens T cell APC V V e.g. Staphylococcal enterotoxins
Class II from MHC A to Z haplotypes TcR from MHC A haplotype T cell APC V V 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

35 Interaction of SEB with MHC Class II molecules and the TcR
MHC class II TcR beta chain TcR beta chain SEB MHC class II SEB

36 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 SEB 3, 12, 14, 15, 17, 20 SEC1 12 SEC2 12, 13.1, 13.2 SED 5, 12 SEE 5.1, 6.3, 6.4, 6.9, 8.1 TSST-1 2 Explains why superantigens stimulate so many T cells

37 Effect of TSST-1 on T cells expressing V2
Fresh PBMC unstained Fluorescence intensity (i.e. amount of staining with anti-V antibody) Cell number Fresh PBMC stained with anti-V2 PBMC cultured with TSST-1 Stained with anti-V2 Cell number PBMC cultured with TSST-1 Stained with anti-V3

38 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

39 Superantigens T cell APC Vb V V Mouse mammary tumour viruses (Mtv)
TcR from MHC A haplotype T cell APC Class II from MHC A to Z haplotypes Vb V V Superantigens Mouse mammary tumour viruses (Mtv) Cell-tethered superantigen encoded by the viral genome

40 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)

41 Endogenous superantigen V-relationship
Mtv Murine V region Mtv Mtv Mtv , 5.2, 11 Mtv 6 3, 5.1, 5.2 Mtv 1 3 Mtv 3 3 Mtv Mtv 7 6, 7, 8.1, 9 MMTV SW 6, 7, 8.1, 9 MMTV C3H 14 MMTV GR 14 Stimulate T cells in a similar manner to exogenous supernatigens Valuable tools in analysis of self tolerance

42 Mtv act in a similar manner to exogenous superantigens in vitro
STIMULATOR CELLS Mtv-7 +ve RESPONDING T CELLS Mtv-7 -ve Irradiated T T T APC T T T Mtv-7 superantigen 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

43 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

44 Transmission of infection
2. Massive T cell response to MMTV superantigen 3. Vigorous T cell help leads to B cell proliferation and differentiation to long-lived B cells B 1. MMTV infected, MHC class II positive B cells 4. Infected cells traffic to mammary gland and infect young via milk

45 Analysis of negative selection in vivo.
Mtv Mtv-7 superantigen negative THYMUS 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 Immature CD4+8+ thymocytes expressing VV8.1 and V9 in the thymus Negative selection Negative selection Mature CD4+ or CD8+ VV8.1 and V9 T cells in periphery No mature CD4+ or CD8+ VV8.1 and V9 T cells in periphery PERIPHERY

46 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

47 X Yes X No V14 present? V14 present? Male C3H Female B10.BR
F1 offspring Yes Male B10.BR Female C3H X V14 present? F1 offspring No

48 Deletion of V14 T cells in mice infected with MMTV by milk
+ Foster female B10.BR Young male or female C3H Yes V14 present in fostered pups? + Foster female C3H Young male or female C3H Or B10.BR No MMTV transmitted to fostered pups by infected B cells found in milk

49 Are the signals that induce positive & negative selection the same, or different?
specificity DIFFERENT specificity T H Y M U S Immature thymocytes Positive selection Negative selection Peripheral T cells X

50 Hypotheses of self-tolerance Differential signalling hypothesis
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.

51 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 TcR T cell CD8 Thymic epithelial cell MHC Class I

52 Positive selection PARTIAL SIGNAL 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 TcR T cell CD8 Thymic epithelial cell MHC Class I

53 Negative selection FULL SIGNAL Peptide is an agonist
Thymocyte receives a powerful signal and undergoes apoptosis i.e. the cell is negatively selected and dies. FULL SIGNAL TcR T cell CD8 Thymic epithelial cell MHC Class I

54 The thymus accepts T cells that fall into a narrow window of affinity for MHC molecules
Useless Neglect Useful Positively select Harmful Negatively select Number of cells Low High Affinity of TcR/MHC interaction

55 Positive & negative selection occurs in distinct thymic microenvironments
Cortex Immature double negative & positive thymocytes Medulla Mature single DN Proliferation CD3- DP Positive selection CD3+ TcR+ Cortical epithelial cells Dendritic cells medullary Epithelial cells & Macrophages DP Negative selection CD3+ TcR+ SP CD3+ TcR+ CD8+ or CD4+

56 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

57 } T Illustration of selection using TcR transgenic mice
Generation of transgenic mice T T cell clone with known TcR specificity and MHC restriction Re-implant Analyse offspring for transgene expression. Rearranged  chain cDNA construct Rearranged  chain } Inject into fertilised mouse ovum In TcR transgene-expressing mice almost all thymocytes express the transgenic TcR due to ALLELIC EXCLUSION.

58 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 MHC B DN CD3- DP CD3+ TcR+ Transgenically express MHC A restricted TcR in an MHC B mouse No single +ve cells are present in the periphery SP CD3+ TcR+ CD8+ or CD4+ Thymocytes die at the double positive stage after failing +ve selection due to a lack of MHC A

59 Restriction element and co-receptor expression are co-ordinated
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 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?

60 Double positive to single positive transition
Double positive thymocyte Single CD4+ thymocyte -ve TcR MHC Class I 3 TcR MHC Class II 2 TcR CD4 CD8 CD8 CD4 √ X MHC Class I MHC Class II 3 2 Thymic epithelial cell Instructive model: Signal from CD4 silences the CD8 expression & vice versa

61 Double positive to single positive transition
Double positive thymocyte Single CD4+ thymocyte TcR MHC Class II 2 TcR MHC Class I 3 CD8 CD4 CD8 CD8 CD4 CD4 CD4 √ X MHC Class I MHC Class II 3 2 Thymic epithelial cell Stochastic/selection model: Cells randomly inactivate CD4 or CD8 gene, whilst testing a match of TcR restriction

62 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 T cells: All transgenic T cells proliferate Analyse thymus: All transgenic T cells die by apoptosis Thymocytes activated by antigen in the thymic environment die T cells activated by antigen in the periphery proliferate

63 How do we become self tolerant to these antigens?
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?

64 Nature Immunology November 2001

65 Promiscuous expression of tissue-specific genes by medullary thymic epithelial cells

66 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

67 T helper cells costimulate B cells Two - signal models of activation
Signal 1 antigen & antigen receptor ACTIVATION Th Y B Signal 2 - T cell help CD40 MHC class II and peptide T cell antigen receptor Co-receptor (CD4) CD40 Ligand (CD154)

68 Antigen presentation - T cells are co-stimulated
APC Th Signal 1 antigen & antigen receptor 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.

69 Mechanism of co-stimulation in T cells
1 Antigen Low affinity IL-2 receptor IL-2 IL-2R IL-2 IL-2R Resting T cells Signal 1 NFAT binds to the promoter of of the a chain gene of the IL-2 receptor. The a chain converts the IL-2R to a high affinity form Express IL-2 receptor-  and  chains but no a chain or IL-2

70 Mechanism of co-stimulation in T cells
2 Costimulation 1 Antigen Signal 2 Activates AP-1 and NFk-B to increase IL-2 gene transcription by 3 fold Stabilises and increases the half-life of IL-2 mRNA by fold IL-2 production increased by 100 fold overall IL-2 IL-2R 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

71 1 Anergy Antigen Naïve T cell Signal 1 only
IL-2 IL-2R 1 Antigen Signal 1 only 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. Self peptide epitopes presented by a non-classical APC e.g. an epithelial cell

72 Arming of effector T cells
Clonal selection and differentiation APC T IL-2 How can this cell give help to, or kill cells, that express low levels of B7 family costimulators? 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

73 Effector function or Anergy?
Clonally selected, proliferating and differentiated T cell i.e. ARMED sees antigen on a B7 -ve epithelial cell This contrasts the situation with naïve T cells, which are anergised without costimulation The effector programme of the T cell is activated without costimulation Armed Effector T cell CD28 Co-receptor TcR IL-2 Armed Effector T cell Naïve T cell Kill Epithelial cell Epithelial cell Epithelial cell

74 Costimulatory molecules also associate with inhibitory receptors
CD28 T cell CD28lo Activated T cell Cross-linking of CTLA-4 by B7 inhibits co-stimulation and inhibits T cell activation - 2 Signal 1 + CTLA-4hi B7 B7 CD28 cross linked by B7 Co-stimulation induces CTLA-4 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.

75 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 APC No danger Apoptotic cell death. A natural, often useful cell death. Innocuous challenge to the immune system fails to activate APC and fails to activate the immune system Fuchs & Matzinger 1995

76 DANGER The danger hypothesis APC
Necrotic cell death e.g. tissue damage, virus infection etc Pathogens recognised by microbial patterns APC DANGER APC that detect ‘danger’ signals express costimulatory molecules, activate T cells and the immune response

77 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 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. Doesn’t exclude self-nonself discrimination, but the danger hypothesis will be very hard to disprove experimentally.

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