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Normal function of CTLA4: limiting T cell costimulation

Normal function of CTLA4: limiting T cell costimulation. T cell activation eventually gets down-modulated by expression on activated T cells of CTLA4, which competes for binding to B7 and which carries an inhibitory signal. CTLA4-deficient mice.

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Normal function of CTLA4: limiting T cell costimulation

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  1. Normal function of CTLA4: limiting T cell costimulation T cell activation eventually gets down-modulated by expression on activated T cells of CTLA4, which competes for binding to B7 and which carries an inhibitory signal.

  2. CTLA4-deficient mice • Mice die at 3-4 weeks of systemic T cell activation and infiltration of multiple organs • Elevated antibodies, and autoantibodies

  3. Absence of costimulation leads to T cell tolerance T cells encountering antigen on non-activated professional antigen presenting cells become inactivated inactivated

  4. Self antigens perceived in the context of costimulation fail to prevent anergy and lead to stimulation • Antigens recognized with low affinity or those that are not present in the thymus do not lead to thymic deletion. • But T cells that recognize self antigen in the periphery can be tolerized in the absence of costimulation. • On the other hand, induction of costimulation by inflammation can break self-tolerance. • Classic example: original rabies vaccine. Vaccine was made from ground up spinal cords containing rabies virus. Immunized individuals developed neurological disease. • The same thing happens when normal spinal cord tissue is injected with adjuvant.

  5. Disease can also be induced by immunizing (in adjuvant) with a single peptide from myelin basic protein Induction of EAE(experimental allergic encephalitis), a model for multiple sclerosis Immunization with many self antigens can lead to autoimmunity, depending on 1) the "strength" of adjuvant 2) genetics of the mouse (MHC plus other genes)

  6. CD4 T cells drive the pathogenesis of EAE Isolate CD4 T cells

  7. Regulatory T cells • Discovered relatively recently, though hints were in the scientific literature for decades. • Cells carry CD4 and CD25, along with TCRab. • Regulatory T cells are able to inhibit T cell responses by interacting with APCs at the same time as antigen reactive T cells. • While the mechanism of action is not well understood, there are several compelling reasons to believe that regulatory T cells may play an important role in preventing autoimmunity.

  8. Figure 13-14

  9. Regulatory T cells IL10 TGFb others?

  10. Regulatory T cells, cont. • Mice thymectomized at day 3 of life have T cells, but they develop multiorgan autoimmune disease. • Rats or mice depleted of certain mature CD4 T cell subsets (CD4+CD25+ in mice) develop inflammatory bowel disease. • In both cases, reintroduction of the "missing" CD4 T cell subset (CD25+) leads to prevention of disease. • Humans and mice mutant in the transcription factor Fox3P develop a severe autoimmune disease. In humans IPEX (immunodysregulation, polyendocrinopathy, and enteropathy, X-linked). In mice, scurfy mutation. • Fox3P is currently the definitive marker for regulatory T cells and may be a master regulator of their development.

  11. How are regulatory T cells (Tregs) made and educated? • Tregs require the thymus for development. • Tregs appear to be positively selected, but bind self peptide with intermediate affinity (i.e., too little to be negatively selected, but with higher affinity than the major T cell populations that are positively selected). • The current hope is that manipulating Tregs may allow treatment of existing autoimmune disease in an antigen specific way.

  12. Epidemiology of autoimmunity Genetics - Many genetic loci affect the predisposition to autoimmune disease. By far the most important is the HLA locus Gender - In specific autoimmune diseases (SLE, MS), females are more commonly affected Environment - Studies in identical twins shows that there is >20% concordance in monozygotic twins, and < 5% in dizygotic twins

  13. The strongest genetic association with disease maps to the MHC Type I diabetes (Protection)

  14. HLA association with type I diabetes

  15. Suceptibility to insulin dependent diabetes (IDDM) appears to be strongly increase in people carrying a particular HLA-DQ chain combination: the a chain of DQ8 and the b chain of DQ2. The nature of the key autoantigen is under intensive investigation.

  16. Role of the environment Celiac disease is caused by T cell response to food peptide linked to a self protein Peptide linked to self protein, Transglutaminase Contains altered peptide

  17. Celiac disease T cells also help autoreactive B cells that see transglutaminase-coupled to gluten peptide. Antibodies to transglutaminase are diagnostic of celiac disease.

  18. Rheumatoid arthritis Autoantigen unknown

  19. Figure 11-13 Anti-TNF therapy of rheumatoid arthritis

  20. Figure 11-36

  21. Some autoimmune diseases are caused by cross reactivity between microbial and self antigens

  22. Figure 11-30

  23. Figure 11-31

  24. Clonal ignorance Express a flu viral protein as a transgene in the pancreas under the insulin promoter regulation. Mice are tolerant of the pancreatic beta cells until challenge with the virus, at which time they attack the pancreas.

  25. Figure 11-32

  26. Figure 11-37

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