Lecture # 17 T Cell Receptor Signaling, T Cell Priming, and Peripheral Tolerance

Question 1

TCR activation leads to three different intracellular signaling pathways. What are they?

Answer 1

NF-kb, NFAT, and AP-1; converge on IL-2 gene production

Question 2

Z proteins and ITAMS

Answer 2

contain 3 ITAMs per tail

Question 3

How do co receptors enhance phosphorylation of TCR?

Answer 3

T cell binds to antigen in the context of MHC causing phosphporylation of ITAMs, coreceptors strengthen that interaction; LCK phosphorylates ITAMS when the co-receptor binds MHC, Fyn is also recruited and leads to more phosphorylation of CD3 complex, Zap-70 is recruited, binds it ITAMS and becomes phosphorylated.

Question 4

What is the role of LCK in IL-2 production?

Answer 4

LCK phosphorylates ITAMS, which leads to binding and phosphorylation of ZAP-70

Question 5

What is the role of ZAP-70 in IL-2 production

Answer 5

Once phosphorylated by LCK, binds to ITAMs then phosphorylates LAT, which phosphorylates PLCg

Question 6

What is the role of PLCg in IL-2 production?

Answer 6

PLCg hydrolyzes membrane phospholipids converting PIP2 to produce IP3 and DAG; PLCg acts through Ca++ and DAG to activate NFAT and NF-kB

Question 7

What is the role of IP3 in IL-2 production?

Answer 7

Binds to IP3 receptors on ER, causing the release of calcium

Question 8

What are the three signals for activation of naive T Cells?

Answer 8

signal #1 - TCR binding; signal #2 co-stimulation (sends signals to allow the cell to proliferate and increase survival); signal #3 third signal consists of cytokines and these drive differentiation of naive CD4 cells.

Question 9

Three Co-stimulatory molecules

Answer 9

B7-1 on DC/APC (CD80); B7-2 on DC/APC (CD86), CD28 (present on the T cell that binds B7-1 and B7-2)

Question 10

How does co-stimulation (B7 to CD28) influence IL-2 production?

Answer 10

Co-stimulation #1 increases the secretion of IL-2 and expression of IL-2R, which is important for cell proliferation; #2 produces BCl-Xl, BCL-2 #3 also increases levels of NF-kB, AP-1 to increase mRNA production and stabilize IL-2 mRNA

Question 11

What is the function of BCL-XL and BCL-2?

Answer 11

Both produced when B7-CD28 interact. Function as cell survival signals.

Question 12

What is the difference between naive non-activated and activated T cells?

Answer 12

1) Naive T cells express IL-2R bg low affinity signaling portion of the receptor 2) Activated T cells express the high affinity R, a complex of IL-2R, a, b, and gc, IL-2 induces IL-2Ra.

Question 13

CTLA-4

Answer 13

Expressed on activated T Cells; also binds to B7-1 and B7-2 on the APC; sends a negative inhibitory signal to the T Cell to limit the proliferation response of antigen specific cells; produces proteins that block IL-2 pathway;

Question 14

What are the three consequences of TCR signaling in the absence of co-stimulation?

Answer 14

1 Activation ( Ags activate lymphocytes leading to the generation of immune response against that antigen) , # 2 tolerance (upon recognition of antigens, lymphocytes may become functionally inactivate or killed resulting in tolerance, #3 ignorance (Antigen specific lymphocytes may not react to antigens and the lymphocytes may simple ignore the presence of antigens.

Question 15

What happens to a T cell that receives a specific signal (signal 1) only

Answer 15

Inactivates T cell; anergy

Question 16

Tolerogenic

Answer 16

Ag promote anergy of T cells (CTLA-4) resulting in functional unresponsiveness.

Question 17

immunogenic

Answer 17

Ags promote activation of T cells (B7-CD28)

Question 18

Why is it important that IL-2 is produced?

Answer 18

IL-2 is responsible for growth and differentiation of naive T cells.

Question 19

What cascade leads to the activation of AP-1

Answer 19

MAP kinase cascade.

Question 20

What leads to the activation of NF-kb?

Answer 20

PLCg activates DAG, DAG activates PKC, PKC activates NF-kB leading to IL-2 production.

Question 21

Is LFA-1 an important adhesion molecule in APC-T cell interaction. If so, how?

Answer 21

T cells initially bind to APC with low affinity; if the TCR binds to MHC, LFA goes to high affinity interaction

Question 22

What are the three signals involved in the activation of Naive T cells?

Answer 22

1) TCR binding 2) costimulation (CD28/ B7-1 (APC) promote growth and survival 3) cytokines signals drive proliferation

Question 23

What does CD28 signaling promote?

Answer 23

Overall, enhances signaling through the TCR; produces Bcl-Xland BC-2 for survival; increases secretion of IL-2 and upregulation of IL-2R to increase proliferation; increases levels of NF-kB and AP-1

Question 24

Is there a difference between the IL-2R receptor on naive and activated cells? If so, how?

Answer 24

naive cells express low affinity IL-2Bgc receptor; activated T cells express high affinity R IL-2Rabgc

Question 25

What is the role of CD69?

Answer 25

Aids in the retention of the T cell in the lymph node

Question 26

What is the role of IL-2R?

Answer 26

Proliferation

Question 27

What is the role of CD40L?

Answer 27

Activation of DCs, Macrophages, and B cells

Question 28

What is the role of CTLA-4?

Answer 28

Control of the immune response

Question 29

AICD

Answer 29

Activated induced cell death; recognition of self antigen results in the production of pro-apoptotic proteins Bim/ or Fas:FasL

Question 30

Tregs

Answer 30

Regulatory T cells; kept alive by signals from foxp3 and IL-2; generated in the thymus, but cause tolerance in the periphery.