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3 signal model of activating T cells
- A. TCR bind to MHC-peptide
- B. costimulator (CD28, ICOS)
- C. cytokine-cytokine receptor induce cell differentiation
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Naive T cells develop into 4 activated T cell populations
- A. CD4+ à Th: secrete cytokines
- B. CD8+ à CTL: lyse target cells
- C. NK T à secrete cytokines
- D. NK à lyse target cells
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3 naïve T cell surface molecules target to lymph node
L -selectin, CXCR4, CCR7 target to HEV of lymph node
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4 Molecular adhesion bonds allow T cell sampling of APC surface
- LFA 1 (CD11/CD18) to ICAM1 (CD54)
- ICAM1 (CD54) to LFA 1 (CD11/CD18)
- VLA4 to VCAM
- CD2 to LFA3
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Key components of T cell—APC interactions
- A. APC presents peptide-MHC Class 1 to CD8+ T cells
- B. APC presents peptide-MHC Class 2 to CD4+ T cells
- C. 3-5 agonist peptide-MHC on APC surface is sufficient for activation of T cell
- D. TCR amplifies signal via endocytosis recycling and serial engagement of new TCR with peptide-MHCs
- E. T cell CD28 binds to B7.1/B7.1, which is expressed on activated APCs only
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steps in Signal 1 of T cell activation: TCR binding to peptide-MHC
- A. TCR conformation change upon binding with antigen-MHC
- B. CD3 activate Lck (Src kinase)
- C. Lck phosphorylate ITAMs (immunoreceptor tyrosine-based activation motifs)
- D. Biphosphorylated ITAMs bind to ZAP70/Syk
- E. ZAP70 phosphorylation activate LAT
- F. Phosphorylated LAT binds and activates SLP76, vav, PLCγ1
- G.PLCγ1 hydrolyzes PI3Pà IP3 + DAG
- H. IP3à increase Ca2+ à activate calciuneurin à activate NFAT (nuclear factor of activated T-cells)
- I. DAGà MAP kinase cascade
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5 variations of ITAM signaling pathway
- Receptor: receptor component
- TCR: CD3 γε, δε, ζζ
- BCR: Igα, Igβ
- NK activating receptors: DAP12
- Fc receptors: FcγRIII
- Neuronal receptors: CD3 ζ, ε
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Signal 2 of T cell activation: CD28 mediated
- A. APC B7.1/B7.2 binding activate CD28 pathway
- B. CD28 tyrosine residues are phosphorylated
- C. PI3K and other proteins associate with CD28-Pi
- D. PI3K facilitate NFκb activation
- E. Increase mRNA stability of cytokines produced by T cells
- F. Slow activation CTLA-4, which competes with CD28 for B7.1/B7.2 binding; prevents T cell from activating out of control
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Signal 1 alone leads to...
anergy, cell is rendered inactive to prevent autoimmunity
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2 Secreted factors mediating T cell activation
- IL2 autocrine growth factor
- IL4 mediates T cell activation of B cell antibody response
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3 surface molecules expressed after CD4+ T cell activation
- IL-2R=CD25: receive IL2 growth signal
- S1P1: allows egress from lymph node and thymus to infected tissue
- CD154=CD40L: interact with CD40 on B cell to promote isotype switching
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Digeorge syndrome
- 22.q11.2 deletion
- no T cell in thymus
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Chronic variable immunodeficiency disease (CVID)
CD19, ICOS, TACI mutation
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hyper IgM syndrome
- CD40, CD40L, AID, UNG mutation
- no isotype switching in B cells
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X linked agammaglob or auto recessive ARA
Btk/mu, λ5, Igα, Igβ, BLNK
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FTY720 targets ___
S1P1, which allows activated T cells to egress form LN/thymus to infection site
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Rapamycin targets ___
- IL2, IL2R
- which is the growth factor signal for T cells
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cyclosporin and FK506 targets ___
calcineurin, which is a phosphatase that activates NFAT
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normal WBC cell count
- WBC=4400-8100
- Myeloid= 2/3
- Lymphocyte= 1/3 (1400-3300)
- neutrophil= majority of myelocyte 1800-7700
- Monocytes<800
- Eosinophils<450
- Basophils <200
- B cells (CD19+)1100-1570
- T cells (CD3+) 1000-2200
- CD4+ T cells 530-1300
- CD8+ T cells 330-920
- NK cells 70-480
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