Immuno T cell Subsets (7/8)

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Immuno T cell Subsets (7/8)
2013-10-17 13:47:26

Exam 3
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  1. Immuno 7
  2. Processing
    • the catabolism of protein into peptides inside a host cell
    • some peptides will go on to bind to MHC molecule
  3. Presentation
    • a peptide & MHC are presented on the surface of a host cell
    • will go on to be recognized by a TCR on either a CD4+ or CD8+ T cell
  4. exogenous antigens
    • pathogens are taken up by specialized host cells, APCs, and are not pathogenic but still foreign
    • “harmless” antigens
  5. endogenous antigens
    derived from inside a host cell as a result/product of the cell being infected by a foreign pathogen
  6. exogenous antigen processing
    • occurs using MHC class II pathway (eg. dendritic cells, macrophages)
    • 1. antigen is taken into acid vesicles & broken down into peptides
    • 2. vesicles containing broken down peptides merge with vesicles containing newly synthesized MHC class II molecules
    • 3. peptide-MHC class II is presented on the surface of the cell to CD4+ T cells
  7. endogenous antigen processing
    • occurs using MHC class I pathway
    • 1. antigen catabolized (degraded) in cytoplasm by proteasome
    • 2. peptides transported to ER
    • 3. peptides associate & selectively bind to newly made MHC class I molecules (still happening in the ER)
    • 4. peptide-MHC class I complex moves from the ER to the golgi & is presented on the surface of the cell for interaction w/ CD8+ T cells
  8. What size peptide can bind to an MHC class I complex?
    • peptides must be 8-9 amino acids long
    • this length fits into the peptide-binding groove of the MHC class I molecule
    • there are fewer peptide size restraints in respect to MHC class II molecules (can have 12-20 AA long peptides binding)
  9. What effect does Interferon gamma (IFNγ) have on antigen processing pathways?
    • it can up-regulate both MHC class I & II processing
    • in contrast, viruses/tumors can down-regulate processing, especially endogenous in MHC class I presenting cells
  10. What happens when an antigen peptide does not bind to an MHC molecule?
    it does NOT trigger an immune response
  11. cross-presentation
    mechanism by which dendritic cells can showcase peptides derived from exogenous antigen processing & present them to CD8+ T cells
  12. What does the selectivity of peptide binding to certain HLA molecules and huge diversity of HLA molecules help to explain?
    • upside: the combination of HLA & peptides invoke a protective response in response to certain diseases (eg. malaria)
    • downside: the large diversity sometimes confers pathology in those particular individuals who have HLAs that are anti to self peptides
    • there's an evolutionary advantage
  13. What is required but not sufficient for an APC to activate a CD4+ T cell?
    • MHC class II presenting a peptide expressed on the APC surface
    • TWO SIGNALS TOTAL are required for CD4+ T cell activation
    • signal #1: MHC class II + peptide --- TCR
    • signal #2: between costimulators
  14. Costimulators
    • molecules required in addition to the TCR to activate naïve (have not yet encountered antigen) T cells via signal transduction
    • costimulators on T cell surface interact with molecules on the surface of an APC to provide a costimulator (2nd signal)
    • eg. CD28 (T cell) --- B7 (APC)
    • CD40 Ligand/CD40L/CD154 (T cells) --- CD40 (APC)
  15. How do costimulators come about on APC & T cell surfaces?
    • APC: induced AFTER exposure to pathogen
    • T cell: some up-regulated during response
  16. What is the key APC for the activation of naïve T cells?
    the dendritic cell
  17. _______ induce maturation of dendritic cell in tissue
    • pathogens induce maturation of dendritic cell in tissues
    • phagocytosis and antigen processing of pathogens up-regulates MHC class II & costimulators, changing the surface of the dendritic cell
    • causes DC to migrate out of tissue --> the draining lymph node

  18. Adjuvant
    • a molecule (frequently synthetic) that upregulates costimulators & TLRs on APCs to give primary response a boost
    • necessary because many harmless molecules do not produce an immune response
  19. Events in T cell Activation
    • 1. CD4 moves closer to TCR & pulls with it kinases
    • 2. activated Zap-70 sends a message & activates 3 different sets of pathways
    • 3. transcription factors are activated --> move into nucleus and transcribe genes (occurs within ~72 hours after initial activation)
  20. Which (3) key genes are transcribed during T cell activation?
    • 1. cytokine genes (*IL-2)
    • 2. cytokine RECEPTOR genes (IL-2Rα chain)
    • 3. homing molecule gene expression is changed (cell surface molecules that influence where cells moves in body)
  21. What occurs as a result of the change in expression of homing molecule genes?
    activated T cells leave the lymph node and move into tissues, generally at the site where pathogen was first encountered
  22. IL-2
    • T cell growth factor
    • the binding of IL-2 to its high-affinity receptor (IL-2R) expressed on activated T cells results in huge proliferation & clonal expansion of antigen-specific T cells
  23. What does the costimulator pair B7 --- CD28 function to do?
    • it stabilizes IL-2 mRNA
    • in the absence of this signal, IL-2 mRNA is rapidly degraded
    • (B7 on the APC/DC, CD28 on the T cell)
  24. Cyclosporine A is fungal metabolite used to prevent graft/transplantation rejection. How does it accomplish this?
    • it complexes with calcineurin, INHIBITING T cell activation & preventing cytokine synthesis that activates effector cells to reject the foreign tissue
    • calcineurin: phosphatase that ACTIVATES T cells
  25. Effector T cell
    • cell that is now ready to exert its function
    • the change in honing & adhesion molecules on the surface of the cells as a result of gene rearrangement transforms a naive T cell --> effector T cell
  26. Immuno 8
  27. CD4+ T cells
    • which synthesize and secrete a vast array of cytokines
    • act as helper cells for B cell antibody synthesis, & CD8+ T cells, which directly kill cells
  28. cytokines are pleiotropic
    • one cytokine can act on many different cells
    • many different cell types can make the same cytokine
  29. What are 3 different ways cytokines can exert their effects?
    • 1. autocrine = affects the same cell
    • 2. paracrine = affects nearby cells
    • 3. endocrine = secreted into the circulation
  30. Interleukin 4 (IL-4)
    • TH2 cytokine that induces B cells to syntheze IgE
    • synthesized by CD4+ T cells (TH2), mast cells, & others
    • (anti-IL-4 agents used to treat some forms of asthma)
  31. IL-5
    • TH2 cytokine that activates eosinophils
    • anti-IL-5 agents used to treat some forms of asthma
  32. Interferon-γ (IFN-γ)
    • signature TH1 (a CD4+ T cell subset) cytokine that activates NK cells & macrophages to participate in cell-mediated immunity & kill infected cells of the body
    • also induces B cells to switch to synthesizing antibody isotypes that activate complement (key effector pathway in the response to many types of bacteria)
  33. Tumor necrosis factor-α (TNFα)
    • activates cells in the inflammatory response
    • synthesized by macrophages and NK cells
    • (anti-TNFα agents are used to combat rheumatoid arthritis)
  34. What are the 4 major subsets of cytokine-synthesizing CD4+ T Cells?
    • TH1: IFNγ, IL-2
    • TH2: IL-4, 5, 13
    • TH17: IL-17, 22
    • Treg: TGF-β, IL-10

  35. What cytokines and effects does the CD4+ T cell subset TH1 have during an immune response?
    • cytokines: IFNγ, IL-2
    • act on macrophages, NK cells, CD8+ T cells, B cells to make IgG3
    • cell mediated immunity
    • killing of virus/bacterially infected host cells

  36. What cytokines and effects does the CD4+ T cell subset TH2 have during an immune response?
    • cytokines: IL-4, 5, 13
    • act on eosinophils, B cells to make IgE & IgG4
    • respond to WORMS & allergens

  37. What cytokines and effects does the CD4+ T cell subset TH17 have during an immune response?
    • cytokines: IL-17, 22
    • act on neutrophils, epithelial cells (especially at mucosa)
    • are pro-inflammatory & respond to fungi/extracellular bacteria
  38. What cytokines and effects does the CD4+ T cell subset Treg have during an immune response?
    • cytokines: TGF-β, IL-10
    • act on other lymphocytes to INHIBIT the function of other sets of T & non-T cells
    • (Treg cells themselves express CD25)
  39. Where do the cytokines that drive the differentiation of naïve CD4+ T cell into a particular subset (TH1, TH2, TH17, or Treg) come from?
    • cells of the innate immune system, particularly dendritic cells
    • innate immune system cells shape the adaptive immune response
    • IL-12 --> TH1 cell development
    • IL-4 (source unclear) --> TH2 cell development
  40. cytokines synthesized by one CD4+ T cell subset inhibit the development or function of other subsets
    • this results is a skewed pattern of the CD4+ T cell responses
    • IFNγ & IL-2 made by TH1 INHIBIT TH2's from making IL-4, 5 & 13
    • (the reverse applies as well)

  41. Helper T cells (follicular T helper cell, Tfh)
    • CD4+ T cells that interact with B cells to induce antibody synthesis
    • occurs in secondary lymph node germinal centers
    • CD4+ T cells are required for most B cells to synthesize antibody in response to a TD-antigen
  42. linked recognition
    • how in response to a TD antigen the cooperating Helper T & B cell may respond to different parts (epitopes) of a single antigen peptide, but the epitopes are part of the same protein
    • this linked recognition occurs in the germinal center of secondary lymphoid organs (eg. lymph nodes)
  43. TD-antigen B cell activation
    • 1. BCR (B cell receptor = antibody) binds to antigen
    • 2. antibody/antigen complex is taken up by cell
    • 3. antigen is broken down in acid compartments to smaller peptides
    • 4. specific antigen peptides bind to MHC class II
    • 5. peptide-MHC class II complexes are trafficked to the cell surface
    • 6. here it interacts with a CD4+ T cell that has the matching TCR for the antigen peptide (1st signal…)
    • 7. CD4+ T cell CD40L binds to B cell CD40 (2nd signal) -->
    • B cell makes antibody & T cell is activated to proliferate cytokines

  44. What two CD4+ T cell derived cytokines induce class-switch recombination?
    • TH2 made IL-4
    • TH1 made IFN-γ

  45. What defects can cause hyper-IgM syndrome?
    • 1. nonfunctional CD154 (CD40L) in boys, X- linked hyper-IgM syndrome
    • 2. defective CD40
    • 3. defective AID (enzyme required for class switch recombination)
    • *any defect in CSR --> hyper IgM syndrome
  46. thymus independent (TI) antigens
    • important antigens don't require helper T cells to make antibody
    • these include polysaccharides/lipopolysaccharide components of bacterial cell walls
    • responses to TI antigens don't normally produce T cell-derived cytokines, B cells do not undergo Ig class switch
    • only IgM is synthesized
    • IgM is not expressed on B memory cells, memory B cells DO NOT develop from TI antigens
  47. What are two bacteria that produce TI (thymus independent) antigens & therefore create no memory B cells after infection?
    • 1. Hemophilus influenzae
    • 2. Streptococcus pneumonia
  48. conjugate vaccines
    • purified capsular polysaccharide from the bacterium conjugated to a protein --> generate T cell epitopes
    • allow bacterial components that usually make TI antigens to be recognized by appropriate TCRs, generating a thymus DEPENDENT immune responses in which B cell class switching occurs & memory develops
  49. CD8+ T cells
    • kill host cells that have been infected by pathogens, particularly viruses
    • commonly referred to as cytotoxic T lymphocytes (CTL) or killer T cells
    • play a role in transplantation rejection and the destruction of tumor cells
  50. effector cells
    • CD8+ T cells that have emerged from the thymus and been activated
    • occurs via the same two-signal paradigm
    • #1 peptide/MHC class I interact w/ TCR
    • #2 costimulator signals
  51. What is required in the responses to most viruses (eg. HIV)?
    activation of virus-specific CD4+ T cells is required for the activation of virus-specific CD8+ T cells
  52. What two new events occur upon CD8+ T cell activation?
    • 1. formation of granules that contain cytotoxic proteins
    • 2. expression of the cell surface molecule Fas ligand (FasL or CD95)
  53. CD8+ T cells Kill via Two Pathways
    • 1. contents of granules in activated CD8+ T cell pass into the target cell --> activate apoptotic mechanisms --> cell death
    • 2. interaction of Fas Ligand (CD95) on the CD8+ T cell with Fas on the target cell --> apoptoses the target cell

  54. What are the major granule constituents involved in CD8+ T cell target-cell killing?
    • perforin: molecule that polymerizes to form ring-like transmembrane pore in target-cell membrane
    • granzymes: pass into target cell through perforin made pores & interact with intracellular components to induce apoptosis
  55. What is a signal that TERMINATE CD8+ T cell activation?
    • 1. induction of CTLA-4 (CD152) on activated T cell surface
    • CTLA-4 (CD152) competes with CD28 to bind to B7 on APC surface
    • unlike the CD28-B7 interaction, B7-CTLA-4 transmits a negative signal to the activated T cell, turning off the response
    • [CTLA-4 (CD152) can be used in therapies, such as melanoma, to dampen T cell response]
  56. Memory Cell
    a lymphocyte – a CD4+ or CD8+ T cell or a B cell – that has been stimulated by antigen (in a primary response) and that is activated in a second or subsequent response by the same antigen
  57. Thymus Dependent (TD) Antigen
    an antigen that requires T helper cells to cooperate with B cells to synthesize antibodies
  58. Thymus Independent (TI) Antigen
    an antigen that does not require T helper cells for B cells to synthesize antibodies
  59. Which antigens trigger which responses?
    • • Infectious pathogens (TD) – eg. viruses and bacteria
    • CD4+ T cells, CD8+ T cells, antibody (IgM, IgG, IgA or IgE) & γδ T cells (especially mycobacteria)
    • • “Harmless” TD antigens – eg. vaccine protein
    • CD4+ T cells & antibody (IgM, IgG, IgA or IgE)
    • • Worms and allergens
    • CD4+ TH2 cells & IgE antibody
    • • TI antigens – eg. bacterial polysaccharide
    • IgM
    • • Tumors
    • if immune response is made, predominantly CD8+ T cells (NK, if no MHC class I expression)
    • therapies = enhance immune response (by injecting tumor antigens expressed on DC (prostate cancer), or inhibiting turn off signals)