Santangelo - T Cells

Question 1

Clonal selection hypothesis

Answer 1

• The lymphocyte precursor cell matures and generates many different types of naive T cells.
• they make their way to the secondary lymphoid organs such as lymph nodes and the spleen where they are introduced to specific antigens.
• If one of the T cells is a good match to an antigen present then that T cell will be cloned many more times.

Question 2

T Cell receptor recognition of peptide-MHC complex

Answer 2

The T cell Receptor does not only recognize the peptide within the MHC complex, but it actually also recognizes some of the AAs that are on the MHC as well.

Question 3

Co-stimulating of T cells

Answer 3

Signal 1 is the MHC/Peptide complex and the TCR
Signal 2 is B7 from the dendritic cell with the CD28 of the T cell.
- IMPORTANT - when the dendritic cell is activated it up regulates B7 (As well as MHC) on its surface in order to increase co-stimulation.

Question 4

How does the co-stimulation using B7 create tolerance?

Answer 4

Because only in true attacks are the dendritic cells activated to express B7 on their surface. It is possible usually that you can have MHC molecules expressing peptides. Without the co-stimulator though nothing will happen.

Question 5

WHy is co-stimulation. An. Issue in cancer?

Answer 5

Because they are out own cells, the dendritic cells will not be activated and therefore there will be a lack of B7. This is because it is our own cells. The MHCs will still be presenting our peptides, but without co-stimulation, nothing will happen.

Question 6

How are T cells turned off???

Answer 6

A molecule called CTLA-4.

• this molecule is up regulated shortly after the T cell is activated and it comes to the cell surface.
• it binds B7 in order to disrupt co-stimulation and therefore there will be no T cell response.

Question 7

How is CDLA-4 involved in treatment?

Answer 7

They give a soluble version of CDLA-4 that is not bound to anything. It will then float around and eventually bind to the dendritic cells B7 so that there is no co-stimulation and thus lessening of the immune response.
- used to treat autoimmunity or overactive immune systems.

Question 8

How can we manipulate CTLA-4 to treat people with tumors?

Answer 8

We can add something that blocks CTLA-4 from interacting with B7, so the immune response is prolonged. Therefore the tumor can have a better chance of being cleared.
- YERVOY - ipilimumab

Question 9

Components of T cell receptor complex

Answer 9

You have the alpha and beta chains which are on the outside that interact with the antigen.
Then we have to have something on the inside to relay the message, that is called CD3 (epsilon and gamma chains). We also have a zeta chain to do this.
Attached to CD3 and the zeta chain we have these ITAMs.

Question 10

Early signaling events in T cell activation

Answer 10

1) When there is a ligand attached to the alpha and beta portion of the T cell receptors, the ITAMs gets phosphorylated by an enzyme called LCK.
2) ZAP-70 then binds to the phosphorylated tyrosines, which then itself causes ZAP-70 to be phosphorylated. ZAP70 then goes on to phosphorylate and activate an enzyme called LAT

Question 11

ICAM/VCAM

Answer 11

Adhesion molecules found on the dendritic cells that help the TCR bind to the dendritic cells.

Question 12

We know that MHC Class II molecules activate CD4 cells. What happens next?

Answer 12

They can either become Th1, Th2, or Th17 cells depending on what they are fighting.

Question 13

Th1

Answer 13

Produces IFN-gamma and is involved in macrophage activation.

Question 14

Th2

Answer 14

Secreted IL-4, IL-5, and IL-13
Involved in allergic responses and fighting off parasites.
- mast cell, eosinophil activation

Question 15

Th17

Answer 15

Secreted IL-17A, IL-17F- and IL22

Involved in inflammation and organ specific autoimmunity

Question 16

Treg

Answer 16

Another possible outcome from CD4. It is responsible for inhibiting T cell activation. There are various mechanisms in which this occur that we don’t have to know.

Question 17

SIV

Answer 17

The viruses act on the peptide so that the “anchor” amino acids that are supposed to fit into the pocket of the MHC are mutated and therefore the peptide can’t be presented on the cell surface and thus CD8 T cells are not activated.

Question 18

T Cell Development

Answer 18

First you have every combination of T cells with various TCRs in the thymus.
Then there is positive selection where only like 5% of the thymocytes have useful T cells with useful TCRs
Then there is negative selection where of the ones with useful TCRs, some have TCR that bind too tightly so they are killed off too, leaving only a handful.

Question 19

Central Tolerance

Answer 19

When the affinity is too tight they are killed in the thymus.

Question 20

WHere do T cells mature?

Answer 20

They start on the outside of the. Thymus and. Slowly move into the middle of the thymus as they mature more.

Question 21

How does the thymus change with age? WHat is the consequence of this?

Answer 21

The thymus will shrink as you get older. The consequence of this is That there will be less thymocytes being made and thus less T cells will be made.

Question 22

T cell activation.

Answer 22

• We have our naive T cells, which are T cells that have yet to be exposed to an antigen.
• once the naive T cell is exposed to an antigen it likes it begins to proliferate. It makes effector cells and memory cells.
• the effector cells are what will actually clear the infection and they make IL-4 and IFN-gamma
• memory T cells are long lived cells that are antigen specific and will respond quickly upon reexposure.

Question 23

Ipilumimab

Answer 23

Binds to CTLA4 and doesn’t allow it to turn of T cells. Increased immune activity and killing of cancer cells.

Question 24

What are the basic mechanisms of Tregs?

Answer 24

Inhibitory Cytokines
Targeting dendritic cells
Cytolysis
Metabolic disruption