02282013 - 2 - T-Cell Activation And Function

Front 1

Naive vs. effector T-cells

Back 1

- Naive have not encountered Ag's
- Effector cells - have seen Ag's, differentiated to helper or cytotoxic

Front 2

2-signal activation process for naive T-cells

Back 2

- Matching MHC-Ag complex
- Co-stimulatory signal from same APC
- CD28 on T-cell sees B7
- This ensures they only get activated by APC's

Front 3

Professional APC's

Back 3

- Dendritic, Macrophages, B-cells
- All express B7 - can give the co-stimulatory signal

Front 4

Effect of co-stimulation

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- Like turning both missile keys
- T-cell becomes activated -> Only needs to see MHC-Ag complex to act

Front 5

Anergy purpose, mechanism

Back 5

- Negative selection not perfect - keeps auto-immune cells in check
- Unresponsiveness of T-cell resulting from encountering Ag without co-stimulation
- Even if sees Ag in APC afterwards, it won't respond!
- Die from neglect...

Front 6

Activated cell IL-2 response

Back 6

- Naive cell has very low level IL-2 receptors
- Activated cells upregulate IL-2 receptors AND IL-2 itself and surrounding cells
- Self-stimulated growth!

Front 7

Effector T-cell types overview

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- CD8 -> cytotoxic T-cells
- CD4 -> T-reg or Helper T-cells
- Variety of helpers for all different pathogens...

Front 8

Cytotoxic T-cells (CTLs)

Back 8

- Derived from CD8 cells, see MHC I
- Kill virus, tumor, or any other cell presenting foreign peptides via MHC I on surface

Front 9

2 CTL killing mechanisms

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1) Direct toxin delivery
- Cytotoxins stored in lytic granules
- TCR engagement -> Perforin opens a hole in cell
- Granzymes -> cleave caspases -> Apoptosis
2) Fas-FasL pathway
- Fas on target cell is stimulated by the FasL on CTL
- Stimulates apoptosis

Front 10

2 methods to avoid killing innocent bystanders

Back 10

1) Activated cells are stimulated by TCR
- Normal cells have nothing to fear
2) CTL's align themselves with target cell when releasing granules
- Very precise release of granules

Front 11

Cathepsin B purpose

Back 11

- Resists perforin and Granzyme B binding to CTL itself!
- Avoids killing itself!

Front 12

CD4 T-cell differentiation process

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- Naive CD4 cell activated by APC with MHC II
- Th0 = activated, still undifferentiated, branch point
- IL-12 from APC -> Th1 cell -> IFN-γ
- Macrophage activation, inflammation
- IL-4 from APC -> Th2 cell -> IL-4,5,13
- B-cell switch to IgE
- Eosinophil activation
- Mast cell stimulation
- Mostly for parasites...not much use to us...

Front 13

Th1 macrophage activation

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- Resting macrophages are lazy, activated ones -> extremely bactericidal
- IFN-γ and CD40L on Th1 - activate macrophage

Front 14

Activated macrophage products

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- Express more CD40 and TNF receptor - more sensitive
- TNF-α
- NO
- O2- radicals (kill bacteria)
- Upregulate MHC I, II, B7
- Activate naive T-cells

Front 15

Activated Th1 products

Back 15

- IFN-γ and CD40L = activate macrophages to destroy bacteria
- Fas ligand = stuffed macrophages apoptosis
- IL-2 - increase number of active effector cells
- IL3 - more macrophage differentiation in marrow
- TNF-α and β = endothelial opening for macrophage migration
- CXCL2 = chemotaxis of macrophages to infected area

Front 16

Granuloma formation

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- Poor IFN-γ production
- T-cells can't effectively activate macrophages (or macrophages aren't disposing of bacteria)
- T-cells gather around clump of macrophages

Front 17

Th2 differentiation, products, and action

Back 17

- IL-4 causes Th0 -> Th2
- Th2 produces IL-4,5,13
- IgE switching
- Eosinophil, mast cell stimulation
*** Macrophage INACTIVATION

Front 18

Main Th2 activity in the US

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- Allergic reactions!
- We don't really get worms...

Front 19

Th17 activation, action

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- Activated by IL-6, TGF-β
- Makes IL-17
- Neutrophil recruitment and inflammation
- Good for bacterial, yeast, fungal
*** Can also promote auto-immunity

Front 20

Th17/IL-17 diseases

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- Upregulated in multiple sclerosis, arthritis, etc.

Front 21

Follicular helper cell (Tfh) activation, action

Back 21

- Activated by - IL-6 from APC, IL-21 from other T-cell
- Action = helps B-cells in germinal centers to produce high-affinity antibody!

Front 22

Induced T-reg cells (iT-reg) activation, action)

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- Activation = only see IL-2 and TGF-β from other T-cells
- Action = make IL-10, TGF-β, IL35
- Suppress immune response
- Bad = can supress normal function too much...

Front 23

Th9 activation, action

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- Activation by IL-4 and TGF-β
- Action - make IL-9
- Promotes mast cell activity like Th2
- Can produce inflammatory allergic responses

Front 24

Th1 inhibition actions

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- Produces IFN-γ, negatively regulates Th2 and Th17

Front 25

Th2 inhibition actions

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- Produces IL-4, negatively regulates Th1 and Th17

Front 26

T-reg and FoxP3+ cell inhibition actions

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- Produce IL-10 and TGF-β
- Negatively regulate APC function, Th1 and Th2

Front 27

5 Post-infection T-cell reducing agents

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- CTLA-4
- Activation-induced Cell death (AICD) - Fas and TNF pathways
- TGF-β (inhibit lymphocyte activation)
- IL-10 (inhibit macrophage activation)
- Regulatory T-cells - potent immunosuppressive action

Front 28

CTLA-4 on all active T-cells

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- stimulates Immunoreceptor Tyrosine-based Inhibitory Motif (ITIM)
- Binds B7, directly competes with CD28
- Turns off CD28 stimulation, can halt attack by T-cell

Front 29

Activation induced cell death (AICD) - via Fas

Back 29

- If too many T-cells in crowded area
- Tend up upregulate FasL
- Basically induce apoptosis in eachother

Front 30

T-reg cells

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- Express FoxP3 - unique to T-reg cells
- 5-10% of peripheral CD4 cells
- Immunosuppressive - make IL-10, TGF-β, IL-35

Front 31

IPEX syndrome

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- Lack of T-reg cells (mutations in FoxP3)
- Fatal autoimmune disease
- X-linked

Front 32

Clinical applications of T-reg manipulation

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- Enhancing/decreasing response for autoimmune disorders or cancers

Front 33

Cyclosporin A (CsA)

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- Inhibits T-cell activation
- Causes reduced production of IL-2

Front 34

T-cell activation in absence of Csa

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- Signals to T-cell activate NFAT
- NFAT goes to nucleus, upregulates IL-2
- More IL-2 -> more T-cell activation

Front 35

CsA inhibition mechanism

Back 35

- NFAT can't get phosphorylated
- Can't upregulate IL-2

Front 36

Protective immunity

Back 36

- Requires memory T-cells and B-cells
- Allows faster response than activating all-new naive cells