Lecture 5 - T cell activation

Question 1

How do T cells which have survived positive and negative selection in the thymus become effector T cells or memory T cells?

Answer 1

1. T cells go into circulation and then enter secondary lymphoid tissues, eg lymph node, via high endothelial venules (HEV).
2. T cells recognise antigen on MHC presented on APC and become activated. This activation requires 3 signals. The T cell then becomes an effector T cell and will go to the target cell.
3. If T cells do not become activated, they leave lymph node via cortical sinuses, back into circulation.
4. All 3 of these steps require cell adhesion molecules (CAMs) to mediate cell-cell interaction.

Question 2

How do T cells enter secondary lymphoid tissues from blood?

Answer 2

Via high endothelial venules (HEV)

Question 3

How do inactivated T cells in the secondary lymphoid tissues get back into circulation?

Answer 3

via cortical sinuses

Question 4

What are Cell Adhesion Molecules (CAM)?

Answer 4

Molecules expressed on T cell surface ( chemokine receptor) that bind ligands (chemokines) expressed by other cells. This mediates cell-cell interaction which is needed to get T cells into lymph node via HEV, to help bind T cells with APC, and effector T cells with target cells. CAMs are very important!

Question 5

For T cells to become activated, they have to bind to MHC class 2 molecules on APCs. How do they bind/ interact? (remember CAMs)

Answer 5

1. initially bind via low affinity LFA-1: ICAM-1 interactions. LFA (leukocyte function-associated antigen), ICAM (intercellular adhesion molecules).
2. If T cells recognise MHC molecule, the affinity of CAM increases, and the cell- cell contact is prolonged. This means contact can be withheld through the activation process.

Question 6

T cells require 3 signals from APCs in order to become activated. what are these 3 signals?

Answer 6

1. When naive T cells contact the MHC/peptide molecule on the APC, a the first signal is released. This involves the CD3 z chain.
2. Signal 2 is released when co-stimulatory molecules B7.1/2 bind to CD28 on T cells.
3. Signal 3 is released when cytokines released by APC bind to cytokine receptors on T cells.

Question 7

What does the first signal of T cell activation involve?

Answer 7

CD3 zeta chain

Question 8

To prevent the T cell response getting out of control, activated T cells express a molecule to dampen down the immune response. This will help to reduce things like cancer. What is this molecule and what is its role?

Answer 8

> CTLA-4 is expressed by T cells and has a higher affinity for B7.1/2 that CD28 on T cells. Therefore CTLA-4 displaces CD28 and acts as an antagonist, dampening down the immune response, inactivating T cells.
Mutations in CTLA-4 can cause autoimmune diseases as there is over expression of T cells.
To target cancer, anti-CTLA-4 treatments can enhance immune response to tumour, as it increases the amount of T cells to that tumour.

Question 9

Once T cells are activated, they express ICOS on their surface. What does ICOS do?

Answer 9

ICOS binds to ICOSL on APC cells, and induces T cells to secrete cytokines.

Question 10

B7.1/2 binds to CD28 on T cells in the activation of T cells. B7.1/2 can also bind to other co-stimulatory molecules. What are these? (separate for B7.1 and B7.2)

Answer 10

B7.1 - CD80

B7.2 - CD86

Question 11

How does the innate response induce activation of the acquired immune response?

Answer 11

Pathogen associated molecules bind to PRR on APC molecule, activating it. This activation leads to the danger signal, which leads to up regulation of MHC and co-stimulatory molecules (needed for activation of T cells). This ensures signal 2 will activate T cells only during infection, when there actually is a pathogen there.

Question 12

Signal 3 of T cell activation involves APC cells releasing cytokines which bind to receptors on the T cell. Each cytokine will cause a difference differentiation of CD4+ cells. Which cytokines cause which T cell to be made?

Answer 12

T reg cells - TGF- beta

Tfh Cells - IL-6

Th17 Cells - TGF- beta, IL-6

Th1 cells - IL-12, IFN-gamma

Th2 cells - IL-4

Question 13

Dendritic cells are the most common APC. What are the two types of dendritic cells?

Answer 13

1. Myeloid ( conventional DC 2,3)
   involved in activation of naive T cells.
2. Plasmacytoid DC (pDC, DC6)
   important in viral infection. They secrete several Type 1 an and beta interferons and express TLR 7 and 9.

Question 14

Describe what happens to a dendritic cell during infection.

Answer 14

1. immature dendritic cells in the peripheral tissue recognise PAMPs on pathogen (eg bacterial LPS) by PRR on the surface of them. LPS binds to TLR on dendritic cell. TLR signalling induces CCR7 which stimulates phagocytosis.
2. Recognition of PAMPs by PRR causes a danger signal, so the dendritic cell migrates to lymph node, where the T cells are. CCR7 directs this migration. Once in lymph node, dendritic cell expresses MHC molecules and co-stimulatory molecules eg B7.
3. Mature dendritic cell can then activate T cell.

Question 15

What is special about some specialised DC cells eg DC1?

Answer 15

DC1 cells can take up exogenous Ag and present it on an MHC class 1 molecule. This allows DC cells to active CD8+ T cells.

Question 16

What are 3 important APCs?

Answer 16

1. dendritic cell
2. macrophages
3. B cells (Ag specific APCs)

Question 17

Why is the cytokine IL-2 important for T cells?

Answer 17

Activated T cells express a high affinity IL-2 receptor and secrete IL-2. When IL-2 binds to IL-2R on surface of T cell, proliferation of T cell is induced.

Therefore, IL2 is an important cytokine for T cell proliferation.