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Immunology, too strong binding of MHC: TCR --> they will become…

- - - - MBL binds to MASP
    - - antibody binds to microbe. C1 (C1qr2s2) binds to antibody
        
        circulating c4 --> c4a + c4b
        
        C4a
        
        C4b
        
        reacts w -OH -NH2
        
        circlulating c2 --> c2a + c2b
        
        c2a
        
        c2b
        
        C3 CONVERTASE (C2bC4b)
        
        C3 --> c3a + c3b
        
        2 more items...
    - - spontaneous hydrolysis C3--> C3(H20)
        
        C3 CONVERTASE: C3(H20)Bb
- - - - In the thymus… naive CD8s are marked by CD45RA+, CD28+, CD27+, CCR7+
        
        do not express granzyme, perforin, or IFNy
      - survival relies on IL-7 and -15 signalling
        
        go through a memory state BEFORE they reach their effector state
      - Naives are found only in periphery or lymph
        
        effectors found in tissues
    - - CM: in lymph organs (CD62L+ and CCR7+)
        
        EM: in circulation (neg. for all)
        
        RM: in tissue (CD103+ CD69+)
    - - activated by Ag recognition on MHC class 1, CD28, and at least one other co-stimulator (CD40, IL12, TLR ligands, or IFNa)
        
        Signal 1 and 2 w/o Signal 3:
        
        expansion w/o effector functions
        
        tolerance
        
        Higher regulation necessary bc of potent cytotoxic effects
        
        response is maintained only when Ag and IL-2 are present
    - - generated when all 3 signals are received
      - GOAL: deposit toxic granules into target cell for killing
      - Transient interactions: LFA1/2/3 and ICAM1
        
        ICAM1 and LFA1 form pSMAC around MHC/TCR/CD28 complex
        
        Cytolytic products secreted through synapse
        
        Granules contain perforin, granzymes, phosphatases, and cathepsins
        
        perforin pokes holes in membranes
        
        granzymes cleave caspases 3 and 8... apoptosis
        
        Granules are too large to fit through the pore
        
        most likely enter the cell via endocytosis or granzyme receptor
        
        expression of FasL can also induce target cell death
        
        Indirect killing: INFy and TNF
  - - - tolerance acquired by mature lymphocytes in peripheral tissue
      - Central tolerance is incomplete
        
        autoreactive cells can still be present
      - Deletion
      - Ignorance
        
        restricted migration of naive cells
        
        can't enter tissues to encounter Ag
        
        Negative selection kills off most autoreactive T cells
        
        SHOULD be low affinity, if encountering self-Ag
        
        positive selection prevents TCRs with strong affinity from leaving the thymus
        
        Lack of other signals: costimulation, adhesion, or cytokines
      - Deviation: alter T cell response to prevent autoimmunity
    - - TF: foxp3
        
        Transcriptional profile: CTLA-4, Blimp1, Ikaros, STAT3/5, NFAT
        
        IL-2
        
        sustains T cell activation... Vital for FoxP3 expression and TReg survival
    - - Trogocytosis: vacuum clean APCs without using MHC presentation
      - Cytokine secretion: IL-10 and TGFb
      - Cytolysis: granzyme or perforin
      - disrupt metabolism: CD25, tryptophan, adenosine
      - preferable binding to DCs
    - - FoxP3 -/- develop fatal autoimmune disorders
        
        FoxP3+ Tregs actively:
        
        prevent diabetes in NOD mice
        
        prevent IBD
        
        promote transplant tolerance
    - - FoxP3- Tregs that produce IL-10 and TGFb
      - induced by priming T cells in the presence of IL-10, immature DCs, and repeated stimulation
- - - - only found in tissues, so they’re hard to come by
        
        Die rapidly when removed from tissue
        
        If they don’t die, they radically change their gene expression
        
        We don’t understand their ligands well
        
        They’ve rapidly evolved to have species-specific subsets
        
        Hard to compare findings in mice with humans
    - - gd TCR develops during DN3 via VDJ recomb. in the thymus
        
        d-chain first... genes w/in TCRa locus
        
        TCR less diverse than ab TCR
        
        fewer gene seg. and common pairings (vg9+vd2)
      - gd TCR recognizes lipid antigens
        
        no role for negative selection bc it can't recognize MHC
- - - - SP: CD4+ CD8+
        
        Checkpoint 2: TCR checking
        
        CD4+ : Th cells, ThPOK
        
        CD8+: Tc cells, RUNX3
        
        +VE SELECTION
        
        -VE SELECTION
        
        NEGLECT
    - - death
  - - - 2: CD34+, CD38+
        
        3: CD34+, CD38+, CD1a+
        
        4: CD4+, CD3lo
  - - - 2: CD44+, CD25+
        
        3: CD44lo, CD25+
        
        4: CD25+