Immune Regulation

Question 1

Why is IL-2 such a crucial cytokine?

Answer 1

It has autocrine and paracrine function to allow growth and differentiation of itself and the adjacent cells (T and non-T)

Question 2

What are the three CRUCIAL surface molecules that are uporegulated after T-cell activation?

Answer 2

CD40L- to activate B-cells (give signal 2)
VLA4 - to traffic to the infected tissue
IL-2- to allow differentiation of the T and non-T cells in the area

Question 3

By what order of magnitude to T cell populations expand upon activation?

Answer 3

1-3 orders of mag

Question 4

What is a cytokine storm?

Answer 4

large releases of cytokines that overstimulate the innate AND adaptive immune system (IFN and TNF) leading to systemic inflammation

Question 5

What cell releases IL-12? What type of cell does it usually affect and what is the result?

Answer 5

Macrophages and DCs release it to increase NK cells and to convert T-cells into Th1

Question 6

What transcription factor has a rapid spike within the first hour or two of the infection to allow proliferation of T-cells?

Answer 6

c-Fos

Question 7

What occurs during the initial phase of an immune response to influenza?

Answer 7

There is a rapid mobilization and activation of effector T-cells (you will see max level of CD40?, IL-2, IL-2R)

Question 8

Starting at about 12 hours and peaking at 3 days, what event reaches its maximum level?

Answer 8

DNA synthesis because T-cells are dividing and making copies

Question 9

Starting at about 4 days post infection, the levels of 3 molecules start to rise. These molecules contract the T-cell response. What are they?

Answer 9

1. Fas
2. CTLA-4
3. PD-1

Question 10

What is the general role of CTLA4?

Answer 10

It outcompetes with CD28 to bind B7-1/B7-2 (CD80/86) essentially blocking signal 2 for T-cell activation

Question 11

What is the basic role of Fas?

Answer 11

When Fas on a T-cell encounters fasL there is a potent fas-mediated cell death signal and the cell dies

Question 12

Why is there a spike in VLA4,5,6 about a week after the infection?

Answer 12

This is the homing molecule of effector and memory T-cells to recirculate them

Question 13

After a viral infection is contained and the number of infected cells is decreased, there is a _____________________ in the number of influenza specific T-cell numbers.

Answer 13

dramatic reduction

Question 14

When antigen specific T-cells are reduced after an infection is cleared, do they go back to base level?

Answer 14

No because some will become memory cells. (1 specific T-cell–>1000s–>about 200)

Question 15

What are the four major mechanisms that account for the decrease in effector T-cells?

Answer 15

1. Reduced IL-2
2. Upregulated Fas
3. Expression of inhibitory molecules (CTLA4)
4. differentiation of effector cells to memory cells

Question 16

What is the effect of removing IL-2 after an infection is cleared?

Answer 16

Many of the effector T-cells starve and go through apoptosis

Question 17

What is the effect of upregulating Fas, PD-1 and CTLA4 after clearing an infection?

Answer 17

These reduce activation potential of more T-cells

Question 18

What do CTLA4 and PD-1 elicit in the cell to stop T-cell activation?

Answer 18

They release phosphatases which de-phosphorylate key signalling molecules rendering them inactive

Question 19

If there is a deficiency in Fas or fasL, what disorder will the patient have? What is it associated with?

Answer 19

They will present with ALPS (autoimmune lymphoproliferative syndrome) and will have a lot of CD4-/CD8- T cells

Question 20

What T cell does the transcription factor Foxp3 differentiate?
A mutation in Foxp3 would lead to what?

Answer 20

Treg

A mutation would lead to increased levels of autoreactive cells because Treg checks to ensure cells are not autoreactive before they leave the thymus

Question 21

If the Treg encounters a T-cell that recognizes a self-antigen in the thymus, what does it do?

Answer 21

It inhibits T-cell activation

Question 22

If the Treg encounters a T-cell that is self-reactive in the LN, what does it do?

Answer 22

It released inhibitory cytokines to inhibit the effector functions of the T-cell

Question 23

What are the three ways that Treg maintain peripheral tolerance to self-proteins?

Answer 23

1. inhibitory cytokines (in periphery)
2. inhibiting T-cell activation (thymus)
3. dampening inflammation

Question 24

Tregs are a subset of what type of cell?

Answer 24

CD4+ and is dependent on IL-2 for its survival and development

Question 25

What disorder is caused by a mutation in Foxp3?

Answer 25

IPEX

Question 26

What inhibitory cytokines are secreted by Treg?

Answer 26

IL-10 and TGFb

Question 27

What is an ITIM? What cells would you find these on?

Answer 27

Immune Tyrosine Inhibitory Motifs found in NK cells, T-cells, and B-cells
They are tyrosine phosphorylated after specific receptor cross-linking and then associate with phosphatases that remove phosphates from tyrosine kinase dependent signaling molecules

Question 28

What are the major phosphatases used to turn off lymphocyte activation signal cascades?

Answer 28

SHP1, SHP2, SHIP

Question 29

What two surface molecules on the B-cell have ITIMs?

Answer 29

FcgammaRIIb and CD22 (binds SHP-1 and SHIP)

Question 30

For intense inflammatory responses, what dose of IVIG is appropriate?

Answer 30

1-2g/kg

Question 31

How does IVIG sialylated alpha2-6 suppress the immune system?

Answer 31

It upregulates inhibitory Fc receptors on macrophages and monocytes

Question 32

What does a mutation in fas/fasl result in?
What is the disorder called?
What will the patient present with?

Answer 32

lymphoproliferative diorder in which the cells are activated and expand without control.
ALPS (lots of DN cells)
They present with splenomegaly (because of the excess of lymphocytes in the spleen)

Question 33

APECED results from a mutation in what?

Answer 33

AIRE which presents self-tissue from other parts of the body to T-cells in the thymus to ensure they are not autoreactive

Question 34

What problem is associated with IPEX? It is a mutation in what TF?

Answer 34

immune system that destroys itself because it lacks Treg