Immune tolerance. Lu,Linrong Institute of Immunology, ZJU

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1 免疫耐受 Immune tolerance Lu,Linrong Institute of Immunology, ZJU g

2 Immunological Tolerance *Definition *History (Early observations ) *Mechanism Central Tolerance Peripheral Tolerance *Induction (Acquired tolerance)

3 Definition Immune tolerance or Immunological tolerance' is the process by which h the Immune system does not attack an antigen. Specific immunological unresponsiveness to a given antigen. It occurs in 2 forms: natural tolerance (self tolerance) and acquired tolerance (induced tolerance).

4 Immune response vs tolerance Immune Response Immune Tolerance Antigen Yes Yes Latency Yes Yes Antigen specificity + + Memory + + Response Strong no or weak Function reject non self protect self

5 Immune tolerance Immune tolerance is an active process which is different fromimmunodeficiency or immunosuppression. Immunodeficiency: A disorder or state in which the Immune system s ability to fight infectious disease is compromised or entirely absent. Overall Inability of the immune system to respond to a broad range of antigens. (genetic reason or AIDS) Immunosuppression: A condition where the activation or efficacy of the immune system is reduced (induced by an immunosuppressant

6 Natural Tolerance (self tolerance): Self tolerance: Individuals normally do not respond to their "self antigens, i.e., they are "tolerant" to self. This is the basis for self- non self discrimination by the immune system to ensure immune system not to attack self. Loss of self tolerance can lead to autoimmunity.

7 Acquired tolerance Induced unresponsiveness to foreign Ags. It can be used to facilitate transplantation or when tolerance is necessary(acquired tolerance)

8 Ray Owen, 1945 Early Observations Dizygotic cattle twins that shared the same placenta were blood cell chimaeras, ie contained blood cells of two different ent haplotypes pes in adults and, - these two haplotypes co-existed in the adults without mutual rejection. Ray Owen

9 Such chimaeric cattle will exchange skin grafts without rejection. Normally, if cells of one of the two haplotypes were transferred to an adult cattle of the other haplotype, these were promptly rejected. Thus, tolerance in the dizygotic twins resulted from the sharing of the placenta in fetal life.

10 Burnet s Hypothesis:(1949) During neonatal stage of life, or when immune system is developing, all Ags present are recognized as self. Immune system becomes tolerant to these Ags.

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12 Early Observations Billingham and Medawar proved Burnet s Hypothesis

13 Chimeric mice Early Observations

14 1960 Nobel Prize

15 Human Immunology Volume 52, Issue 2

16 Immunological Tolerance *Definition *History Early observations *Mechanism *Induction

17 Mechanisms (Earlier ) Central tolerance is the mechanism by which h newly developing T cells and B cells are rendered non reactive to self during their development in thymus and bone marrow.

18 T cell development in thymus

19 T cell development in thymus Thymus MHCII MHCII Periphery Helper CD4sp + CD4T + CD4-8 - CD MHCI MHCI CD8sp + CD8T + Cytotoxic o

20 Stages of thymocytes development

21 Thymocytes are positive selected db by MHC/self peptides Positive selection: During positive selection Double- Positive T cells that can recognize self MHC s are selected for proliferation, and those T cells that do not recognize self MHC die via Apoptosis. Positive selection also assures TCR to recognize peptide/mhc complex and also go with the appropriate CD4 or CD8. For example, TCR s specific for MHC II need to retain CD4, and lose CD8. If the reverse occurs, they will die via apoptosis. The same is true for the T cells that are specific for MHC I, which need to retain CD8, and lose CD4.

22 Central Tolerance is achieved by negative selection Negative selection: T cells that are strongly activated by self MHC plus self peptides p need to be eliminated in the thymus. complex. If they escape this elimination, i they may subsequently react against self antigens, and cause Autoimmune disease.

23 Positive Selection vs Negative Selection Avidity Model: Avidity depends on the affinity of the TCR-peptide/MHC p interaction and the density of the peptide/mhc on the thymic epithelial cell. Avidity determines the strength of signal delivered which dictates the outcome. Stronger signals may mean longer signaling or additional signaling. Deat h by Posit ive Negative neglect select ion selection Signal Int ensit y Avidit y

24 A Cartoon view of positive and negative selection Mixture of clones with different affinity to self antigens Apoptosis by AICD Positive selected Negative selected Apoptosis by neglect Released to Peripheral

25 Summaryof central tolerance In summary, Positive selection selects for those T cells that react with MHC: self antigen. Negative selection eliminates those that react strongly with MHC: self antigen. Thus, successful T cell differentiation selects for MHC restricted TCR's with low affinity for self antigens. Th ti l h i th t T ll th t bi d kl t lf The rationale here is that a T cell that binds weakly to self MHC/self Antigen will not be activated but will be activated by a stronger binding to self MHC/ foreign Antigen

26 Kisielow and von Boehmer HY transgenic mice

27 Harald von Boehmer Harvard Medical School

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29 Apoptosis of negative selected cells are mediated by the Bcl apoptosis pathway

30 Central tolerance Paradox: Deletion of T cells in the thymus requires local expression of the cognate tissue specific antigens (e.g.insulin, MBP). What cell in the thymus is expressing self-proteins? Wh t k thi ti l ll t ll th ti What makes this particular cell to express all these tissuespecific genes?

31 Central tolerance The answer: A large variety of tissue specific proteins are expressed in the thymus by MEC (medullary epithelial cell)

32 Tissue-restrictive genes expressed by MECs But How?

33 Central tolerance AIRE(autoimmune regulator): transcription factor that enables ectopic expression in the thymus of genes usually considered tissuespecific

34 Autoantibodies in AIRE knockout k mice al Norma nockout AIRE kn From M. Anderson, et al. (Laboratory of C. Benoist and D. Mathis). Joslin Diabetes Center and Harvard Medical School; Science 298:1395, 2002

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37 TRAs presentation in thymus

38 Central tolerance Deletion of self-reactive T cells in the thymus Diane Mathis and Christophe Benoist AIRE (autoimmune regulator) is a putative transcription factor g that stimulates expression of many self antigens in in the thymus

39 APECED in human Humans expressing a defective form of the transcription factor AIRE (autoimmune regulator) develop multiorgan autoimmune disease. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) APECED, also known as autoimmune polyendocrine syndrome-type 1 (APS-1) 1), is a polyglandular disorder that classically manifests as spontaneous autoimmunity against the parathyroid and/or adrenal glands, and/or by a mucocutaneous candidiasis infection. Other common ailments include autoimmune forms of premature ovarian failure, hepatitis, anemia, diabetes, alopecia, and vitiligo. It d bl t h th i th t APECED ti t d l It seemed reasonable to hypothesize that APECED patients develop multiorgan autoimmunity because a defect in AIRE prevents or modifies ectopic transcription of genes encoding peripheral tissuerestricted antigens in thymic MECs.

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41 AIRE

42 AIRE research as another research model Tolerance to self developed in thymus. Why? Self-reactive cells deleted in thymus Is self-antigens expressed in thymus? where? MECs can express self antigens. How? AIRE drive the expression of self antigens How can AIRE do such a job? What regulates AIRE

43 B cell tolerance Immature B cells are tested for autoreactivity before they leave the bone marrow

44 B cell tolerance Central B cell tolerance in a transgenic mouse model

45 Peripheral ltolerance (Immune Regulation) Whywe need a peripheral tolerance? Some antigens are not expressed in thymus or bone marrow, which h leads to the possibility to ti trigger immune response. Negative selection is incomplete: Middle to low affinity self reactive clones are released to peripheral and can be activated under certain conditions.

46 Mechanisms (Earlier ) Peripheral tolerance is immune tolerance developed after T and B cells mature and enter the periphery. The cells are controlled through peripheral tolerance mechanisms.

47 Immunological ignorance Antigen sequestration (lens of eye, spermatozoa): Antigen not seen by the immune system. Low MHC expression (i.e. hepatocytes): Lack or selfantigen presentation. Imm nologicall pri ileged Immunologically privileged sites: Other mechanisms

48 Peripheral T cell tolerance Normal T cell T cell CD28 Activated response APC TCR Tcells Anergy Functional APC TCR Off signals unresponsiveness Deletion APC Activated T cell Apoptosis p (activation-induced cell death) Suppression APC Block in activation Regulatory T cell

49 Anergy induced without co-stimulation i *Most tissue cells don t express co-stimulation receptors *Most tissue cells don t express co-stimulation receptors *Professional APCs don t express co-stimulation receptors without activation

50 Peripheral T cell tolerance Activation-induced induced Cell Death(AICD) *Persistent t presence of self-antigen gives repeated stimulation

51 Peripheral T cell tolerance Activation-induced i i d Cell Death(AICD)

52 Defect in Fas or FasL triggers Autoimmunity Fas Fas L Fas+ Fas- Normal Fas L Autoimmunity and lymphoproliferative p disease

53 ALPS Patient: An unusual mutation Healthy female - at 18 months developed cervical adenopathy( 颈淋巴结肿大 ). Biopsy showed reactive hyperplasia Developed anemia with hypersplenism, hematuria, proteinuria and renal insufficiency due to mesangial glomerulonephritis, then primary biliary infiltration. Evaluation at NIH: lymphadenopathy persists, ANA (+) 1:320, CD4 - CD8 - cells 25% of αβ T cells, increased B cells; Fas surface expression is normal Heterozygous Fas splice mutation resulting in loss of exons 3, 4 (AA 52-96) WT Fas PT 2 TM TM del 52-96

54 Peripheral T cell tolerance Regulatory cells

55 Peripheral T cell tolerance IPEX Disease characteristics. IPEX syndrome is characterized by the development of overwhelming systemic autoimmunity in the first year of life. The majority of affected males die within the first year of life of either metabolic derangements or sepsis; a few survive into the second or third decade. Diagnosis/testing. Diagnosis is based on clinical findings. FOXP3 is the only gene currently known to be associated with IPEX syndrome. Approximately 50% of males with IPEX syndrome have mutations identified in FOXP3. Molecular genetic testing is clinically available.

56 Other Peripheral tolerance determinants Cytokines: 1. Limited it supply of pro-survival cytokines (IL7 for T cell and BAFF for B cells); 2. Secretion of suppressive cytokines TGF-beta, IL10 Signaling pathways: Negative regulators including Phosphotases Ubiqutin Ligases

57 Immunological Tolerance *Definition *History Early observations *Mechanism *Induction (acquired tolerance)

58 Immune Tolerance in Clinic 1. Establish immune tolerance will facilitate organ transplantation, reduce the chance or autoimmune disease. 2. Breakdown of immune tolerance to enhance anti tumor immune response or some viral infection which can escape the immune attack by induce tolerance. Autoimmune Disease Tumor Immune + - tolerance Transplantation rejection Infection

59 Antigen determines for tolerance induction

60 Induction of Immune Tolerance 1. Change the route of antigen:oral uptake; vein injection; inject antigen into immune privileged sites; 2. Bone marrow or thymus transplantation; (mimic central tolerance) 3. Desensitization i i (small dose, multiple l stimulation); i 4. Induction of Treg;

61 Break Immune Tolerance (Enhance anti-tumor response) 1. Injection of exogenous antigen (endogenous antigen concentrate too low; 2. Induction of co-stimulation; 3. Blockade of inhibitory receptors ; 4. Adjust cytokine level by recombinant cytokines or antibodies;

62 Summary Definition of immune tolerance: natural vs acquired Central tolerance / Negative selection / Aire Mechanisms to reach peripheral tolerance /AICD /anergy/ Tregs Practical methods to induce and break tolerance