Medical Immunology (Exam II Material) Lecture 5

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Medical Immunology (Exam II Material) Lecture 5
2015-03-11 23:08:52

Antigen Recognition by T Lymphocytes Parham Ch. 5
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  1. What are similarities between T Cells and B cells?
    • T Cells:
    • -are lymphocytes
    • -are apart of the adaptive immune system
    • -recognize and bind antigen through highly variable antigen specific receptors
    • -receptors (TCRs) are composed of Ig domains
    • -(TCRs) achieve antigen specificity and affinity by gene rearrangement
    • -clones express a single unique form of TCR
  2. What are unique properties of T Cells?
    • T Cells:
    • -TCR (T cell receptor) binds and recognizes mainly peptide antigens (B cells Ag/Ab bind diverse biomolecules)
    • -TCR binds peptide:MHC complexes, and NOT isolated peptide (B Cell Ag/Ab can)
    • -TCR genes do NOT undergo somatic recombination/hypermutation or equivalent isotype switching
    • -T cells play many roles in adaptive immune response ( B cells primarily develop into plasma cells and secrete affinity-matured Ab's)
  3. What does MHC stand for and what does it do?
    MHC = Major Histocompatibility Complex

    -used to refer to a region of the chromosome that encodes MHC proteins; also used to refer to MHC proteins

    -a set of cell surface molecules encoded by a large gene family which controls a major part of the immune system-these set of genes are highly polymorphic with hundreds of variants among humans
  4. What is the major function of MHC?
    MHC = Major Histocompatibility Complex

    -major function of MHCs is to bind to peptide fragments derived from pathogens and display them on the cell surface for recognition by the appropriate T-cells
  5. What type of a protein is a TCR (T Cell Receptor)?
    -a membrane bound glycoprotein

    -always membrane bound, never secreted
  6. What is the composition of a TCR?
    -only a single Fab region, so only one binding site

    -consists of one variable region and one constant region which is anchored to cell surface
  7. What feature and functionality does the TCR lack, structure-wise, that B Cell Ab's do not?
    -an Fc region

    -does not function as an effector molecule (in other words, cannot opsonize pathogens or recruit complement)
  8. How many polypeptide chains do TCRs have?
    -two polypeptide chains; TCR alpha and TCR beta

  9. How many domains does a TCR have in each chain?
    • -two domains per chain
    • -a constant (C) domain and a variable (V) domain
  10. What are the alpha and beta TCR polypeptides composed of?
    • -both are composed of C+V Ig domains
  11. TCRs have one Fab region. Where is the N-terminal located?
    -the N-terminal is located on the polypeptide chains that form the antigen-binding portion of the receptor
  12. Where is the C-terminal portion of the TCR?
    -the C-terminal portion of the polypeptide chain forms the transmembrane region and the cytoplasmic tail, so the TCR is anchored to the cell membrane.
  13. What does the TCR antigen binding site recognize?
    -peptide:MHC complexes
  14. The TCR antigen binding site is similar to Ig in that it contains CDR loops. How many?
    -3 CDR (Complimentary Determining Regions) per variable Ig domain
  15. Can TCR's participate in multivalent binding?
    -Yes. Multiple TCRs on T-cell surface bind to multiple peptide:MHC complexes on opposing cell
  16. What is formed as a result of the multivalent binding of a TCR and an opposing cell via the TCR interactions with  peptide:MHC complexes?
    -an immunological synapse
  17. How many T cell clones exist in a given human being?
    10^6 (1000 times fewer than B cells)
  18. How is TCR diversity generated?
    • -gene rearrangement similar to Ig germline segments with V+J segments, and a C segment
    • -except, TCRs do NOT undergo additional change after antigen stimulation
  19. Organization of TCR gene segments in germline configuration is similar to the organization of germline Ig genes, in what ways?
    • The TCR-alpha locus:
    • -similar to light chain in B cells; contains V+J+ C gene segments

    • The TCR-beta locus:
    • -similar to heavy chains; contains V+D+J+C gene segments
  20. RAG enzyme complex is involved in gene rearrangement in TCR's just like in B Cells.

    A. True
    B. False
    A. TRUE

    -junctional diversity is introduced
  21. What happens in the absence of RAG proteins both B and T Cells?
    -causes Severe Combined Immunodeficiency Disease (SCID)
  22. What is happening during SCID (severe combined immunodeficiency disease)?
    -function B and T cells are incompetent because they both require RAG proteins for recombination or rearrangement of germline DNA

    -allows for common infections to become more serious in infants; treated by bone marrow transplant and further interventional therapies
  23. What protein is thought to be the key element in the origin of the adaptive immune system?
    -RAG proteins
  24. Two subunits of RAG recombinase are made ONLY in what type of cells?
  25. Where is it thought that RAG proteins are derived from?

    (transposons can make and move copies of itself in to different chromosomes)
  26. What do transposons code for?
    -transposase; and enzyme that cuts double stranded DNA

    (believed to have become RAG recombinase)
  27. Transposase is believed to have become which enzyme?

    And repetitive sequences recognized by transposase have become...
    -RAG recombinase

    -RSS (recombinational signal sequences)
  28. Where does gene rearrangement occur during T cell development?
    -in the Thymus
  29. How many unique arrangement possibilities exist during combinatorial diversity in T cells?
    10^6 (same as in B Cells)
  30. How many unique arrangement possibilities exist during junctional diversity in T cells?
    • 10^11
    • (as compared to Ig in B Cells 10^7)
  31. What is the total potential diversity due to gene rearrangement in T Cells?
    10^17 to 10^18

    (10^13 is the total in Ig for B Cells; greater diversity in TCR compensates for the lack of being able to perform somatic hypermutation)
  32. After translation, what do TCR's need to be expressed on the cell surface, that would otherwise leave them trapped in the endoplasmic reticulum?
    They would need to interact, or bind with CD3 complex proteins that have cell surface domains + transmembrane regions + intracellular cytoplasmic regions (CD3ε:CD3δ or CD3ε:CD3γ); also ζchain:ζchain dimers

    these transmembrane regions have a negative charge, which promotes association with the positive charge in the transmembrane region of the TCR
  33. What does the ζchain:ζchain dimer consist of?
    transmembrane region + intracellular cytoplasmic signal domain
  34. What does the T Cell Receptor complex consist of, giving the TCR the ability to be expressed on the cell's surface?
    TCR + CD3ε:CD3δ dimer + CD3ε:CD3γ dimer + ζchain:ζchain dimer
  35. What makes γ:δ T-cells different than α:β T-cells?
    γ:δ T-cells peptide genes are encoded by distinct gene loci

    They are NOT restricted to only recognizing peptide:MHC complexes

    Are more abundant in TISSUES rather than circulation
  36. What must be done to create a cell surface peptide:MHC complex?
    pathogen must be "processed" (broken down into small pieces

    peptide must be "presented" (loaded on to MHC and displayed as a peptide:MHC complex at cell-surface of cell that presents the antigen to the cell)
  37. What two classes do T cells come in and what are their functions?
    CD8: cytotoxic T cell that recognizes peptide:MHC class I complexes and induces apoptosis in cells infected with intracellular pathogen

    CD4: T helper cell that recognizes peptide:MHC class II complexes and helps other cells, namely B cells, respond to extracellular infection; stimulate macrophages to phagocytose pathogens and secrete cytokines
  38. What disease targets CD4, selectively killing them?
    HIV (virus that causes AIDS)
  39. Mature T cells can express both CD4, and CD8.

    A. True
    B. False
    B. False

    mature T cells can only express one, CD4 OR CD8
  40. What is the function of MHC class I?
    presents peptides from intracellular pathogens

    presents all times on almost all cells of the body

    only presents peptide to CD8 cells
  41. What is the function of MHC class II?
    presents peptides from extracellular pathogens

    presents at all times only on specific "professional antigen presenting cells", namely dendritic cells and macrophages of the myeloid lineage

    only presents cells to CD4 T cells
  42. What type of three dimensional structure are MHC class I and II?
  43. MHC class I and II are both what type of protein?
  44. MHC class I and II are composed of of what type of polypeptide chains?
    alpha and beta chains
  45. What is structure and characteristics of MHC class I
    • alpha chain:
    • -three extracellular domains; two make up peptide binding site
    • -transmembrane region anchors it to cell surface

    • beta chain:
    • -no extracellular domain
    • -no transmembrane region
    • -referred to as β2-microglobulin
  46. What is structure and characteristics of MHC class II?
    • alpha chain:
    • -two extracellular domains
    • -transmembrane region anchors it to cell surface

    • beta chain:
    • -two extracellular domains
    • -transmembrane region anchors to cell surface

    peptide binding site is formed by combination of one extracellular domain from each of the two chains
  47. Portions of both MHC I and II proteins are composed of what domains?
    Ig domain
  48. What proteins or complexes have Ig molecules?
    • TCR
    • MHC I
    • MHC II
    • CD4
    • CD8
    • CD3 (from TCR complex)
    • Igα
    • Igβ
    • (of course, all of the immunoglobulins)
  49. Ig domain is the most populous family of proteins in the human genome. Approximately how many have been identified?
  50. What is meant by the recognition of peptides by MHC is "promiscuous"?
    a particular MHC molecule can bind peptides of many different amino acid sequences
  51. Peptide binds in a groove on the MHC surface. What are the characteristics of MHC binding?
    peptide must be in linear conformation

    binding is non-covalent, but very high affinity

    • peptide:MHC binding looks like a hot-dog
    • -MHC alpha helices flank the antigen peptide
    • -MHC beta sheet is on the bottom of the antigen peptide
  52. MHC I accommodates peptides that are how long in amino acids?

    ...and how long in MHC II?
    MHC I: 8-10 amino acids long (bun bigger than the dog; ends pinned down in binding site)

    MHCII: 13-25 amino acids long (bun smaller than dog; peptide ends stick out of groove)
  53. MHC class I presents cells from _____ pathogens.
  54. What is the source of antigen peptides that react with MHC class I, and why re they there?
    the source is the cytosol of the host cell

    example, viruses hijack the host cells ribosomes to produce virus proteins; these ribosomes are in the cytosol
  55. What is responsible for breaking down pathogen proteins in the cytosol?
  56. Which proteasome is more likely to bind with MHC class I, Constitutive proteasome or immunoproteasome?
    Immunoproteasome is more likely to bind to MHC I, because NK cells secrete IFN-γ that leads to the expression of immunoproteasome

    comstituative proteasome exists in the absence of infection and IFN-γ
  57. What is required for cytosolic antigen peptides to be transported across the endoplasmic reticulum membrane?
    a transport called TAP (also called an ABC-transporter), is a member of the ATP binding cassette transport family, and requires ATP hydrolysis to work
  58. What health management issues are ABC-transporters responsible for?
    bacterial multi-drug resistance

    cancer resistance to chemotherapy

    cystic fibrosis
  59. MHC I cannot leave the endoplasmic reticulum unless...
    is has bound a peptide
  60. MHC I exists in a complex with the "peptide-loading complex" in the...
    lumen of the endoplasmic reticulum
  61. What does the peptide loading complex consist of?
    proteins that stabilize MHC I heavy chain:β2 micro globulin heterodimer and a TAP transporter
  62. The peptide-loading complex provides many different peptides for MHC I to attempt to bind. What happens if the peptide is too long and won't bind?
    the peptide will be enzymatically trimmed to about 8-10 amino acids in length until it fits
  63. What happens when the peptide:MHC I complex forms in the ER?
    the peptide:MHC I is released from the other proteins and goes to the cell surface via the golgi
  64. Most cell surface peptide:MHC I complexes contain what type of proteins from normal humans?
    self proteins that DO NOT induce a T cell response; cells are tolerant

    a breakdown of tolerance to self-peptide:MHC leads to autoimmunity