Lecture 10 - T-cell mediated responses II

Question 1

Tregs: what do they do, what are the types, and what is their master transcription factor?

Answer 1

Suppress harmful T-cell responses - prevent self-recognising CD4+ T-cells from triggering an immune response

• Foxp3+
• Foxp3-

Foxp3

Question 2

Foxp3+ Tregs: what do they present on their surface, what are the types, and how are they developed?

Answer 2

CD4+ and CD25+

• natural/thymic Tregs (nTregs/tTregs)
• Induced/peripheral Tregs (iTregs/pTregs)

In the thymus:
* two step model
* TGFβ dependent

In the periphery:
* TGF-β dependent - TGF-β, IL-2, retinoic acid, vitamin D (the latter three require TGF-β presence)

Question 3

Tr1 cells

Answer 3

Foxp3-

IL-10?

Answer 4

TGFβ

Question 5

IPEX: what is it and what happens if you have it?

Answer 5

Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome

Malfunctions in Tregs - often result in autoimmune diseased

Question 6

Foxp3+ Tregs: how do they suppress T cells?

Answer 6

• Cytokine dependent
• Induction of effector T-cell death
• Disruption of effector T-cell metabolism
• Targeting of dendritic cells
• Cytokine dependent - produce TGF-β and IL-10, suppressing (through anti-proliferative cytokines) activated T-cells or T-cells becoming activated
• Induction of effector T-cell death - perforin and granzyme secretion to cause apoptosis of T-cells
• Disruption of effector T-cell metabolism - take up IL-2 at a greater rate than CD4+ T-cells through CD25+ so they can’t become activated. Can also produce adenosine from ATP which inhibits energy-requiring T-cells
• Targeting of dendritic cells - CTLA4 binds to CD80 and CD86 (signal 2 of T-cell activation), making it unavailable for T-cells by both downregulating it and transendocytosis.

Question 7

Cytokine dependent T-cell suppression

Answer 7

Produce TGF-β and IL-10, suppressing (through anti-proliferative cytokines) activated T-cells or T-cells becoming activated

Question 8

Induction of effector T-cell death

Answer 8

Perforin and granzyme secretion to cause apoptosis of T-cells

Question 9

Disruption of effector T-cell metabolism

Answer 9

Take up IL-2 at a greater rate than CD4+ T-cells through CD25+ so they can’t become activated. Can also produce adenosine from ATP which inhibits energy-requiring T-cells

Question 10

Targeting of dendritic cells to suppress T-cells

Answer 10

CTLA4 binds to CD80 and CD86 (signal 2 of T-cell activation), making it unavailable for T-cells by both downregulating it and transendocytosis

Question 11

Treg plasticity: are Tregs able to present multiple T-cell TFs, why, and what is a TF that is expressed in all Tregs?

Answer 11

Foxp3+ should be unable to become another type of T-cell - however hybrid Tregs can occur (ie Foxp3 and T-bet)

Hybrid Tregs become hyper specialised to shut down the type it is (T-bet hybrid is specialised to shut down Th1 cells)

GATA3 is expressed in all Tregs

Question 12

CD8+ cells: what is required for its activation, what are the pathways for its activation, and why is the second pathway used most of the time?

Answer 12

To prevent unwanted destruction, dendritic cells present MHC I through self infection presentation or cross presentation

• Direct DC activation, - MHC I, strong costimmulation, then IL-2 (etc) production
• CD4+ induced activation - once CD4+ t-cells are activated, they bind to DCs and promote expression of costimmulatory molecules

Needs much higher costimmulation than CD4+ T-cells so often needs help from CD4+ T-cells for activation

Question 13

CTLs: what are they, what do they do, how is collateral damage prevented, and what is the process of their killing?

Answer 13

Cytotoxic T-lymphocytes - CD8+ T-cells

• Recognise cell(s), programs cell death
• Produce cytokines (ie IFNγ,

Secrete cytotoxic granules directly at the target cell by remodelling its cytoskeleton and pointing its filaments towards the target cell

Cytotoxic granules released:
* Perforin - forms pores in the membrane
* Granzyme - uses holes formed by perforin to enter the target cell and can then induce cell death

Question 14

Granzyme induced cell death pathways

Answer 14

BID pathway:
* BID cleaved
* Truncated BID disrupts MOM
* Cytochrome c released
* Caspase 9 activated
* DNA cleavage - cell death induced

Pro-caspase-3 pathway:
* Cleaves pro-caspase-3 into caspase 3
* iCAD cleaved causing CAD
* DNA cleavage - cell death induced

Question 15

CTLs: what cytokines may that release and what do they do?

Answer 15

• IFNγ to activate macrophages, induce MHC I expression, inhibit viral replication, etc

*

Question 16

iCAD: what is it, what pathway is it in, and what does it produce?

Answer 16

Inhibitory

Pro-caspase-3

(CAD)