L-10 T-Lymphocyte Effector Mechanisms

Front 1

Signals for T Lymphocyte Effector Functions

Back 1

Only require Ag:MHC (Signal 1)

Does not require costimulatory molecules once activated.

Front 2

What signal draws activated T cells out of lymph node?

Back 2

CXCR5 and Sphingosine 1 phosphate (S1P).

Once exit lymph node, T cells stop expressing CCR7 chemokine receptor.

Blocked by the drug FTY720, which inhibits T cell responses and transplantation rejection.

Front 3

How are naive T and B cells drawn into reactive lymph node?

Back 3

T cell lymph node homing receptors:

CCR7 binds to CCL19 and CCL21.

LFA1 binds to ICAM.

L-selectin binds to L-selectin ligand.

Front 4

T cell lymph node honing - chemokines

Back 4

T cells have chemokine receptor CCR7 on surface, which is drawn to chemokines CCL19/21 from lymph node.

B cells have chemokine receptor CXCR5 on surface, which is drawn to chemokines CXCL13 from lymph node.

Front 5

How are effector T and B cells targeted to site of injury?

Back 5

Change chemokine receptors and integrins expressed so that they are attracted to chemokines released at site of injury.

L-selectin changes to E- and P-selectin ligand.

LFA-1 changes to LFA-1 (I-CAM1) or VLA-4 (VCAM-1)

CCR3 changes to CXCR3 (CXCL10)

Front 6

From which vessels do lymphocytes enter and exit lymph node?

Back 6

Enter via blood stream

Exit via efferent lymphatic vessel, to thoracic duct and then to blood stream and periphery.

Front 7

How long does adaptive immune response take to kick in?

Back 7

Bout a week or so

Front 8

Signals for T and B cell directions and duties

Back 8

Selectin - Rolling/tethering. Slows down T cell.

Chemokine - Stimulate/signaling. Signals that there is an inflammatory response nearby.

Integrin - Firm adhesion. Chemokine signal converts integrin from low- to high-affinity state.

Finally leads to diapedesis.

Front 9

Effector function of CD8+ T cell

Back 9

Sense intracellular pathogen (mycobacteria, listeria, cryptococcus, rickettsia). Do not require signal 2. Induce apoptosis and cell death.

Also induce cytokine secretion (IFNy) leading to inflammation.

Front 10

CD8 T cell activation and effector phase

Back 10

Activation - Forms granules with perforins (pore-forming) and granzymes (serine proteases). Requires costimulation with CD28 (or else, anergy).

Effector - Granule exocytosis, does not require costimulation.

Front 11

CD4 T cell help of CD8 T cells.

Back 11

APC can activate both CD4+ and CD8+ T cell at same time (cross-presentation)

CD4 T cells "help" T cells through both binding to the APC.

Uses "DC Licensing" - CD40L (CD4+) binding to CD40 (APC) licenses the dendritic cell to induce a proper CD8+ response via CD27 (CD8+) binding to CD70 (APC)

Patients with hyper-IgM (faulty CD40) also have decreased CD8+ function because CD4+ cannot help CD8+.

Front 12

Mechanisms of cell-mediated immunity by CD8 cells.

Back 12

1. Perforins form pore in target cells, allowing granzymes (serine proteases) to enter. Granzymes activate caspases to induce apoptosis.

2. T cells upregulate Fas-L on surface. Can bind Fas on target cell. Induces apoptosis in target cell via caspase activation.

Front 13

Perforin homology

Back 13

Perforin is structurally homologous to complement C9, part of MAC.

Front 14

Is perforin sufficient to produce apoptosis?

Back 14

Mammalian cells can protect themselves from perforin-induced pores. Perforins and granzymes together is sufficient to induce caspase cascade and cell death.

Front 15

Perforin deficiency

Back 15

HLH (hemophagocytic lymphohistiocytosis)

Fever, splenomegaly, hemophagocytosis, high levels of inflammatory cytokines (IFNy, TNFa)

T cells can make granules but are unable to kill target. Release cytokines including IFNy. Leads to high levels of macrophage activation.

Front 16

Chediak-Higashi syndrome

Back 16

Deficiency in granule exocytosis. Causes inflammatory signals and HLH-like presentation because cannot secrete perforins on to target.

Front 17

Treatment for HLH

Back 17

Anti-IFNy antibody. Macrophages are not activated so inflammatory cytokines are not secreted, mass phagocytosis and clinical presentation is prevented. Increases survival of mice.

Front 18

Can one CTL kill multiple targets?

Back 18

Yes

Front 19

What cytokines do different helper T cells secrete? What cell types do they signal to?

Back 19

Th1 - IFNy, TNFa, lymphotoxin - signal to monocytes/macrophages

Th2 - IL-4, IL-5, IL-13, IL-25, Amphiregulin, IL-10 - signal to eosinophils

Th17 - IL-17, IL-21, IL-22 - signal to neutrophils

Treg - TGFb, IL-10 - suppress T cell

Front 20

What is signal 3 for T cell activatoin?

Back 20

Cytokines present during primary T cell activation.

If T cell exposed to IFNy or IL-12 during activation -> Th1

If T cell exposed to IL-4 during activation -> Th2

If T cell exposed to TGFb, IL-6, or IL-21 during activation -> Th17

If T cell exposed to TGFb or IL-10 during activation -> Treg

Front 21

Downstream functions of Th1, Th2, and Th17

Back 21

Th1 - Intracellular pathogens

Th2 - Extracellular parasites, allergy/asthma

Th17 - Extracellular pathogens, fungi, autoimmunity

Front 22

What transcription factors promote development of helper T cell into each subtype?

Back 22

TFs open up domains of chromatin associates with genes necessary for subtype

Th1 - T-bet

Th2 - GATA-3

Th17 - RORyt

Treg - FOXP3

Front 23

Th1 function

Back 23

Detects typical intracellular pathogens - viruses, mycobacteria, listeria, cryptococcus, rickettsia. Signals via IFNy to monocytes and macrophages to phagocytose.

Front 24

Activation of macrophages by TH1 cells

Back 24

Called Delayed Type (IV) Hypersensitivity

IFNy hyperactivates macrophages leading to phagocytosis, secretion of cytokines, and inflammatory response.

Front 25

Th2 function

Back 25

Secrete IL-4 and IL-5 to drive immune response to typical extracellular pathogens - staphyloococcus, helminths, clostridium. Driven by eosinophils.

Also stimulates allergic response, driven by mast cell histamine relase.

Front 26

Th17 function

Back 26

Secrete IL17 and stimulate (a) neutrophil response and (b) epithelial cell antimicrobial peptide production.

Front 27

Job's Syndrome

Back 27

Also called Hyper-IgE syndrome

Inherited mutations in STAT3, intermediate signalling in cytokine receptor leading to secretion of RORyt, IL-17, IL-22.

In absence of STAT3, no IL-17 function.

Presents with recurrent staphylococcus (extracellular bacteria) and fungal infections (candida).

Unknown how loss of Th17 leads to hyper-IgE.

Front 28

Memory cells

Back 28

Associated iwth more rapid and larger response for both B and T cells. i.e. Memory T cells secrete IFNy within 6 hours rather than 7 days.

Front 29

Lymphocyte response to HHV-3

Back 29

Overtime, lose frequency of T cells for HHV, even if had chicken pox as child (although antibody responses are still good). Can develop shingles.