Oral Immunology - 0531 - L15 - MHC & Ag Recognition

  1. Examples of co-stimulatory molecules
    • B7.1 (CD80) - CD28 (+), CTLA-4 (CD152; -)
    • B7.2 (CD86) - CD28 (+), CTLA-4 (CD152; -)
    • CD40 - CD40L (+)
  2. TCR vs Ig
    • TCR: V&C-alpha (or gamma) + V&C-beta (or delta)
    • Ig: V&C-L + V&C-H
    • Ag recognition site all in the variable (V) region
  3. Superantigens
    • Bacterial and viral superantigens
    • Bind directly to TCR and MHC molecules on APCs
    • Induce much stronger responses w/ much higher frequency of responding cells
    • Use unique binding site other than the ones for the regular Ag for both MHC and TCR, on the side, usually beta-chain of TCR, resulting in robust signal transduction
  4. Superantigens examples
    • Bacterial
    • - Staphylococcal enterotoxins (SEs) -> food poisoning
    • - toxic shock syndrome toxin-1 (TSST-1) -> toxic shock
    • Viral
    • - exogenous viral superantigens
    • - endogenous retroviral superantigens -> deletion in a large family of TCR V-beta; responsible for B cell lymphoma.
  5. The TCR binds antigen and is surrounded by coreceptors like CD4/CD8, CD3, CD28, which are responsible for signal transduction.
  6. T cell activation
    • - CD3 and zeta-chains contain ITAM (immunoreceptor tyrosine-based activation motif) which can be phosphorylated.
    • - Other than TCR, CD4/8 also can dock to MHC, and once that happens, a kinase, Lck is brought to phosphorylate. Fyn can also phosphorylate. ZAP-70 binds to ITAM.
    • - gene transcription initiated following the signal via NF-κβ
  7. B cell activation
    • modulated by a coreceptor complex of at least three cell-surface molecules, CD19, CD21, and CD81
    • Initiated by binding of C3dg-tagged Ag with CD21 -> coligation of corepctors -> CD19 phosphorylated -> ... -> Src-family tyrosine kinases (Lyn, Fyn, ...) activated -> ... -> transcription follows
  8. T cell selection
    • - Occurs in the thymus, to the hematopoietic cells from bone marrow and fetal liver (a primary lymphoid organ), CD4-, CD8-, TCR-
    • - T cells arrive thymus cortex mostly as CD4-, CD8-, TCRab-
    • - then become CD4+, CD8+, TCRαβ low, called double positive
    • - By the time the cells get to the medulla, positive/negative selection occurs: Positive - receive signals to multiply, lose one receptor to become either CD4+ (TH) or CD8+ (killer), TCRαβ+.
    • - the minority come from the primary lymphoid organs, arrive as CD4-, CD8-, TCRγδ+, continue through the medulla w/o much modification
  9. Selection processes in the thymus
    • Positive selection - low-affinity recognition of peptide-MHC complex on thymic epithelial cell -> selected, rescue from apoptosis, conversion to single positive
    • Lack of positive selection - failure to recognize peptide-MHC complex on thymic epithelial cell -> apoptosis
    • Negative selection - high-avidity recognition of peptide-MHC complex on thymic APC (self-Ag) -> apoptosis
  10. Stages of lymphocyte maturation
    • In bone marrow or thymus (primary/generative organ): Stem cell -> pro-lymphocyte -> pre-lymphocyte -> immature lymphocyte. No Ag-dependence until the late part of the last stage when self-Ag dependence develops
    • In peripheral lymphoid organ/tissue: mature lymphocyte -> differentiated effector lymphocyte. Self-Ag dependence becomes foreign Ag dependence.
  11. B lymphocyte subsets
    • B-1 (fetal liver) -> B-1 B cell, carrying IgM and CD5
    • B-2 (bone marrow) -> transitional B-2 B cell (spleen; carrying IgM) -> follicular B-2 B cell (IgM, IgD) or Marginal zone B-2 B cell (IgM, CD21/CR2)
  12. Pathways of apoptosis
    • Extrinsic pathway
    • Intrinsic pathway
  13. Extrinsic pathway - death domain
    • Activation of death domain receptors
    • Best understood death domain proteins are Fas (CD95) and TNFR-1 (receptor for TNF-a)
    • Trimeric Fas ligand (FasL) binds to and trimerizes Fas
    • Clustering of the death domains in the Fas cytoplasmic domains allows Fas to recruit FADD via death domain
    • The clustered death effector domain (DED) of FADD recruit pro-caspase 8 via similar DEDs in the pro-caspase
    • pro-caspase 8 is cleaved to caspase 8 to activate other caspases, like caspases 3, 7
  14. Intrinsic pathway - Cyt C
    • Cyt C normally only found in mitochondria
    • when apoptosis is induced, mitochondria swell and leak, realeasing Cyt C -> binds to Apaf-1 -> activates pro-caspase 9 and 3 -> cleaves I-CAD, releases CAD -> enters nucleus, cleaves DNA
  15. General scheme of intrinsic pathway regulation
    • Apoptotic stim -> sentinels (Bad, Bil, Bid, Bim, p53, PUMA, NOXA)
    • Sentinels activate executioners (Bax, Bak, Bok)
    • Sentinels inhibit protectors (Bcl-2, Bcl-XL, Bcl-W)
    • Protectors inhibit executioners
    • Executioners -> death
  16. Complementarity Determining Regions (CDRs)
    • Hypervariable regions of Ig, BCR &TCR
    • Determine specificity and contact specific ligand
  17. The most variable parts of the T-cell receptor interact with ___________.
    the peptide bound to an MHC molecule
  18. _________ introduces mutations in the rearranged Ig variable regions that improve Ag binding.
    Somatic hypermutation
  19. Locations and subregions of murine and human MHC molecules
    • - DP, DQ, DR are the main humans HLAs for Class II
    • - The main Class I ones are A, B, C, highest polymorphism
    • - Mouse MHC I: D, K, L
    • - Mouse MHC II: I-A, I-E
  20. Certain HLA haplotypes confer disease resistance
    • reduced risk of severe malaria
    • clearance of HBV and decrease risk of chronic liver disease
    • reduced risk of disease development following human T-lymphotropic virus-1 (HTLV-1) infection
  21. Peptide contains ___________ and ________ to bind to TCR and MHC, respectively.
    • T cell contact residues
    • anchor residues
  22. MHC Class I and Class II molecules
    • size of peptide-binding-cleft (non-covalent)
    • MHC I: smaller; 8-11 residues
    • MHC II: bigger; 10-30 residues
    • Binding site for T cell coreceptor
    • MHC I: alpha3 -> CD8
    • MHC II: beta2 -> CD4
    • Polypeptide chains
    • I: alpha and beta2-microglobulin
    • II: alpha and beta
  23. The specificity of the TCR and MHC explains genetic restrictions in antigen presentation
    • MHC restriction of cytotoxic T cells
    • Can only kill something within a specific MHC context
  24. Pathogens and their products can be found in ________.
    either the cytosolic or the vesicular compartment of cells
  25. Cytosolic pathogens for any cell
    • degraded in - cytosol
    • bind to - MHC class I
    • presented to - effector CD8 T cells
    • effect on presenting cell - cell death
  26. Intravesicular pathogens in macrophages
    • degraded in - endocytic vesicles (low pH)
    • bind to - MHC class II
    • presented to - effector CD4 T cells
    • effect on presenting cell - activation to kill intravesicular pathogens
  27. Extracellular pathogens and toxins taken into B cells
    • degraded in - endocytic vesicles (low pH)
    • bind to - MHC class II
    • presented to - effector CD4 T cells
    • effect on presenting cell - activation of B cells to secrete Ig to eliminate pathogens and toxins
  28. Comparing class I vs II pathway
    • Class II made with invariant chain. When the peptide comes in the ER, the invariant chain is knocked off and the peptide loads there and then they go to the cell surface and is presented to CD4 T cell
    • Class I made in the ER, peptide loads on it and then goes to the cell surface presented to the CD8 (antigen is degraded in cytosol, then loads into the TAP)
  29. Different roles of Conventional and plasmacytoid dendritic cells in the immune response
    • conventional: Immature dendritic cells. have costimulatory molecules like B7.1 and B7.2, adhesion molecules like ICAM-1.
    • plasmacytoid dendritic cell: mature, kills. Make TLRs like TLR-7 and 9, and IFN alpha and beta; Don’t process Ag, makes cytokines that kill directly
  30. Processing of exogenous Ag by APC for presentation to MHC Class II
    • Antigenic peptides associate with MHC II molecules in vessels that interact intersect the endocytic pathway on their way to the cell surface
    • go to the lysosome, then present them to the MHC molecule
  31. Cross-presentation and autophagy of antigens
    • cross presentation: a variant. Ag (from extragenous pathogen or inside vesicle) normally should go through the Class II pathway now ends up in the ER and is loaded to Class I, presented to CD8 T cells.
    • Autophagy of self Ag: another variant. cytosolic proteins normally should go through class I passway. autophagy happened and they are taken into auto-phagosome, which then interact w/ CLIP and MIC, eventually presented by MHC II to CD4 T cells.
    • exogenous peptides presented by MHC class I molecules
    • two pathway can work simultaneously in a same cell
    • dendritic cell prime to kill
  33. CD4+ NK T cells
    • NK T cells produce both TH1 (IFN-gamma, IL-2) and TH2 (IL-4, 10, 13) type cytokines
    • NKT Cells enhance CD4+ and CD8+ T cell responses to soluble antigen in vivo through direct interaction with dendritic cells
    • Bear an invariant TCR (iNKT cells)
    • Restricted by nonpolymorphic CD1 expressed on APC
    • CD1-binds lipid Ags: glycolipid, galactosylceramide (GalCer).
  34. NK cells are an early component of the host response to virus infection
    NKC-meidated killing follows the production of IFN-a, IFN-b, TNF-a, IL-12, and precedes T-cell-mediated killing.
  35. Killing by NK cells depends on the balance between activating and inhibitory signals
    • MHC I normally recognized by inhibitory receptors on NK cells which inhibit signals from activating receptors, hence NK does not kill normal cell.
    • Altered or absent MHC I can't turn on the inhibitory signal, NK is triggered by signals from activating receptors. NK is activated and releases granule contents, inducing apoptosis in target cell.
  36. The ligands for the activating NK receptor NKG2D are _________ which are expressed in conditions of cellular stress, the binding ___________.
    • MHC I like proteins, MIC-A, B, RATE1 (include ULBPs),
    • activates a different signaling pathway from that of other activating NK receptors
  37. NK cells can react against cells that do not express MHC class I
    • when MHC I available, recognized by CTL
    • when not, NK cell
  38. Flow Cytometry / Fluorescent-Activated Cell Sorter (FACS) analysis
    • Dye (fluorochrome) labeled Abs that recognize cells of interest are allowed to bind the cells
    • Different cell surface antigens can be labeled with different color decorated Abs.
  39. Peptide:MHC complexes coupled to _______ to form _______ are able to stain Ag-specific T cells
    • streptavidin
    • tetramers
Card Set
Oral Immunology - 0531 - L15 - MHC & Ag Recognition
Oral Immunology - 0531 - L15 - MHC & Ag Recognition