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MHC II
α1
α2
β1
β2
membrane
Peptide-binding cleft• There are two alleles associated
with MS• DR15 • DQ6
• There are two protective alleles • HLA-C554 • HLA-DRB1*11
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MHC II and T cell Interaction
Macrophage
T cell
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TGF-β role in MS
• Does TGF-β promotes pathogenic function of TH-17 cells
• Or, immunoregulatory effects of TGF-β play a role in TH-17 cells sensitivity and suppression
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TGF-β
• Protein for cell (anti)proliferation, differentiation, and other functions in most cells
• Induces apoptosis• Regulation of CD25+ Regulatory T Cell• Differentiation ofCD25+ Regulatory Cell and
TH-17 cell– Blocks activation of lymphocytes
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What evidence do they present in the introduction that will lead them down a questioning path?
• 1. Without IL-23 there is no EAE, there are no CNS cells, does not appear to be TGF-b dependent
• 2. IL-23 drives the production of IL-7 by memory T cells
• 3. TGF-b leads to FoxP3 production which leads to regulatory T-cells
• 4. TGF-b seems to be an initial pathway, IL-23 is later
• 5. TGF-b levels are increased in time of remission
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Overall Objective
• Here, they look at responses of activated myelin-reactive T cells with treatments of IL-23 or TGF-β and IL-6
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Figure 1
• Hypothesis– If activated T-helper 17 cells receive a signal and
lead to the production of IL-17, then both TGF-β/IL-6 and IL-23 will lead to IL-17 production, but only the IL-23 will differentiate into a pathogenic cell.
Activated TH-17 cells respond to IL-23 and to TGF- β and IL-6/ TGF- β and IL-6 abrogate pathogenic function of TH-17 cells
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Activated TH-17 cells respond to IL-23 and to TGF- β and IL-6/ TGF- β and IL-6 abrogate pathogenic function of TH-17 cells
Techniques you will need for Figure 1
EAE Model (Experimental autoimmune encephalomyelitis)
- Mycobacterium tuberculosis H37Ra (killed and desiccated) + PLP (139-151)
-8-10 days
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IL-17
Demyelination!
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Activated TH-17 cells respond to IL-23 and to TGF- β and IL-6/ TGF- β and IL-6 abrogate pathogenic function of TH-17 cells
Techniques you will need for Figure 1
Lymph node collection
-Cultured with IL-23 or TGF- β and IL-6- 4 days
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Activated TH-17 cells respond to IL-23 and to TGF- β and IL-6/ TGF- β and IL-6 abrogate pathogenic function of TH-17 cells
Techniques you will need for Figure 1
Two different mice models: SJL and C57BL/6
-SJL-PLP (139-151)-Relapsing-remitting clinical course
-C57BL/6-MOG (35-55)-Chronic-progressive clinical course
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Techniques you will need for Figure 1
Flow cytometry (Fluorescence-activated Cell Sorter, FACS)
Activated TH-17 cells respond to IL-23 and to TGF- β and IL-6/ TGF- β and IL-6 abrogate pathogenic function of TH-17 cells
IL-17
Anti-IL-17
CD4
Anti-CD4
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FACS Cont’d
Activated TH-17 cells respond to IL-23 and to TGF- β and IL-6/ TGF- β and IL-6 abrogate pathogenic function of TH-17 cells
IL-17 CD4
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Techniques you will need for Figure 1
Thymidine Incorporation
- Proliferation
Activated TH-17 cells respond to IL-23 and to TGF- β and IL-6/ TGF- β and IL-6 abrogate pathogenic function of TH-17 cells
Fig2B
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Fig1A
Activated TH-17 cells respond to IL-23 and to TGF- β and IL-6/ TGF- β and IL-6 abrogate pathogenic function of TH-17 cells
Fig1B
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Figure 1
• Conclusion– Both IL-23 and the combination of IL-6 and TGF-β
produce IL-17– There is a large production of IL-17 with the
combination of IL-6 and TGF-β – Only the IL-23 produced IL-17 causes infection– Difference is due to increased IL-17 production
rather than to increased expansion of PLP-specific cells
Activated TH-17 cells respond to IL-23 and to TGF- β and IL-6/ TGF- β and IL-6 abrogate pathogenic function of TH-17 cells
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Information you will need for Figure 1
EAE model of MS
Activated TH-17 cells respond to IL-23 and to TGF- β and IL-6/ TGF- β and IL-6 abrogate pathogenic function of TH-17 cells
Disease Grade Clinical Symptoms 0 Healthy 1 Flaccid tail 2 Impaired righting reflex and hindlimb weakness 3 Partial hindlimb paralysis 4 Complete hindlimb paralysis 5 Hindllimb paralysis with partial forelimb paralysis 6 Moribund
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Activated TH-17 cells respond to IL-23 and to TGF- β and IL-6/ TGF- β and IL-6 abrogate pathogenic function of TH-17 cells
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Activated TH-17 cells respond to IL-23 and to TGF- β and IL-6/ TGF- β and IL-6 abrogate pathogenic function of TH-17 cells
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Is their data believable?
S2A
Fig1C
Activated TH-17 cells respond to IL-23 and to TGF- β and IL-6/ TGF- β and IL-6 abrogate pathogenic function of TH-17 cells
Table 1
Disease Grade Clinical Symptoms 0 Healthy 1 Flaccid tail 2 Impaired righting reflex and hindlimb weakness 3 Partial hindlimb paralysis 4 Complete hindlimb paralysis 5 Hindllimb paralysis with partial forelimb paralysis 6 Moribund
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Figure 2
• Hypothesis– If activated T-helper 17 cells can diverge down
different pathways, then when we administer the treatment of TGF-β and IL-6 we will differentiate down an alternative pathway from that of the IL-23 pathway leading to different gene expression.
Gene expression profile of cytokine-stimulated T cells
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Techniques you will need for Figure 2
RT-PCR Refresh
- Measuring mRNA levels
Gene expression profile of cytokine-stimulated T cells
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Figure 2Gene expression profile of cytokine-stimulated T cells
Fig2A
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Figure 2Gene expression profile of cytokine-stimulated T cells
Fig2B
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Figure 2
• Conclusion– IL-17f is up-regulated in the presence of IL-23,
TGF- β and IL-6– IL-22 is up-regulated in the presence of IL-23– IL23r is up-regulated in the presence of IL-23
TGF- β and IL-6 abrogate pathogenic function of TH-17 cells
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Figure 2
• Conclusion– IL-17f is up-regulated in the presence of IL-23,
TGF- β and IL-6– IL-22 is up-regulated in the presence of IL-23– IL23r is up-regulated in the presence of IL-23
TGF- β and IL-6 abrogate pathogenic function of TH-17 cells
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Figure 3
• Hypothesis– If there is differential gene expression in the
activated T-helper 17 cells that lead to pathogenesis, then only those cells that are administered with IL-23 will establish an inflammatory response and lead to the entry of those cells into the central nervous system.
TGF- β and IL-6-stimulated cell do not establish inflammation
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Techniques you will need for Figure 3
How is this experiment done differently? (3A)
- Donor cells to a Recipient
Gene expression profile of cytokine-stimulated T cells
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Techniques you will need for Figure 3
What else? (3A)
- Isolated from CNS and Spleen
Gene expression profile of cytokine-stimulated T cells
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Figure 3TGF- β and IL-6-stimulated cell do not establish inflammation
Fig3A
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Figure 3
Fig3B Fig3C
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Techniques you will need for Figure 3
What is happening here? Looks familiar? (3D)
- Proliferation
-So what?-Taggable
Gene expression profile of cytokine-stimulated T cells
Bromodeoxyuridine (5-bromo-2-deoxyuridine, BrdU)
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Gene expression profile of cytokine-stimulated T cells
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Figure 3Fig3D
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Figure 3TGF- β and IL-6-stimulated cell do not establish inflammation
Fig3E
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Figure 3
• Conclusions
TGF- β and IL-6-stimulated cell do not establish inflammation
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Figure 4
• Hypothesis– If TGF-β and IL-6 are not leading T-helper 17 cells
to interleukin inflammatory responses, then when we administer this combination to the TH-17 cells we will observe reduced levels of chemokine production.
TGF- β and IL-6 reduce chemokine production by TH-17 cells
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Figure 4TGF- β and IL-6 reduce chemokine production by TH-17 cells
Fig4A
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Figure 4TGF- β and IL-6 reduce chemokine production by TH-17 cells
Fig4B
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Figure 4
• Conclusions
TGF- β and IL-6 reduce chemokine production by TH-17 cells
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Figure 5IL-10 is upregulated by TGF- β and IL-6 but not by IL-23
• Hypothesis– If IL-10 and TGF-β/IL-6 are leading to protective
effects against EAE, then when we administer TGF-β/IL-6, and not IL-23, to T-helper 17 cells we will see IL-10 production.
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Techniques you will need for Figure 5
Elisa? Yes! What else?(5A)
Magnetic-activated cell sorting (MACS) -Cool
Gene expression profile of cytokine-stimulated T cells
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Gene expression profile of cytokine-stimulated T cells
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Figure 5IL-10 is upregulated by TGF- β and IL-6 but not by IL-23
Fig5A
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Figure 5IL-10 is upregulated by TGF- β and IL-6 but not by IL-23
Fig5B
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Figure 5IL-10 is upregulated by TGF- β and IL-6 but not by IL-23
Fig5C
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Figure 5IL-10 is upregulated by TGF- β and IL-6 but not by IL-23
Fig5D
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Figure 5IL-10 is upregulated by TGF- β and IL-6 but not by IL-23
Fig5E
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Figure 5
• Conclusions
IL-10 is upregulated by TGF- β and IL-6 but not by IL-23
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Figure 6Bystander suppression mediated via IL-10
• Hypothesis– If IL-10 is leading to pathogenic T-helper cell
deactivation through the TGF-β/IL-6 pathway, then when we administer TGF-β/IL-6 and allow the cells time to produce IL-10, we see decrease in EAE score that is not exhibited when IL-10 is inhibited.
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Figure 6Bystander suppression mediated via IL-10
Fig6AFig6B
Fig6C
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Figure 6
• Conclusions
Bystander suppression mediated via IL-10