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Immunology: Week 4 (T Cells Part 2: TCR and T Cell Activation (First…

- - - - Different combinations of gene segments
      - Junctional flexibility
      - Various gene segments available
      - Different combinations of chains (alpha and beta, gamma and delta)
  - - - DN1
        
        DN2
        
        DN3
        
        DN4
        
        DP [CD4+ CD8+]
        
        TCR alpha chain is now functional and replaces the surrogate pre-TCR alpha chain
        
        Both CD4 and CD8 are expressed
        
        +ve and -ve selection occurs yielding mature single positive (SP) T cell
  - - - homologous to Abs
      - +ve charge transmembrane regions to promote interaction w/ CD3
    - - mediates antigen-MHC recognition
      - CD3 (required for surface expression of TCR)
        
        Trimer
        
        ITAM: Immunoreceptor tyrosine-based activation motif
  - - - Signal 1: TCR-CD3 interaction with antigen-MHC complex
        
        TCR and accessory molecules bind MHC-Ag
        
        Phosporylation of ITAMs on CD3
        
        Zap-70 docks on ITAM, LCK (on co-receptor) phosphorylates ZAP-70 intiating various downstream signaling pathways
        
        Co-stimulatory molecules activate or down-regulate T cells e.g. B7 on APC
      - CD4 or CD8 co-receptor minds MHC
        
        Co-receptors/Stabilizing molecules: stabilize binding to MHC, act in signalling process for T cell activation
      - Signal 2: CD28 interacts with B7 molecule (co-stimulatory signal from the APC)
        
        B7 family molecules on APC interact with CD28 on the T cell
        
        Interaction of CTLA-4 (only on active T cells) with B7 down-regulates T-cell activation
- - - - Lectin Pathway
        
        Independent of antibodies // Soluble proteins recognize microbial antigens
        
        Makes C4b2a convertase (more similar to classic pathway)
        
        Lectins bind microbial surfaces and serve as docking sites for specific proteases
      - Classical pathway
        
        IgM and some IgG binding
        
        C1 Macromolecules binds two sites on constanf regions of heavy chains
        
        C3 convertase prevents constant binding of C1
      - Alternative pathway
        
        C3 activation
        
        C3a (enhances inflammation)
        
        C3b (initiates opsonization and lysis through MAC)
        
        Initiated by broad cell surface components
        
        3 modes of initiation that all results in C3 convertase on target surface
        
        Tickover: activated C3b binding to the membrane of the target cell
        
        protease-activated: clotting cascades, cleavage of C3, stabilization of C3b
        
        Properdin-activated: properdin directly binds to target recruiting C3b
        
        C3 CONVERTASE cleaves C3 and binds C3b of the former C3 creating C5 convertase (aka C4b2a3b).
        
        Thioester bond forms between amino groups of target surface. If absent, the bond is hydrolyzed (=non-reactive)
  - - - Classic (staple form of IgM, close proximity of IgG)
      - Alternative: C3b on cell host inactivated by sialic acid
      - Lectin: Host cells have mannose covered by sialic acid
  - - - C5a induces expression of CR1 receptor
- - - - Site of proliferation, differentiation, and selection of cells
        
        Selection: if the receptor binds an MHC molecule it is positvitely selected. If the receptor does not bind the MHC receptor then it undergoes apoptosis.Negative selection prevents autoimmunity