A5: T Cell-Mediated Immunity

Question 1

What are the major steps in T cell activation upon response to an antigen (name 6 steps)?

Answer 1

1. Secretion of cytokines
2. The cytokines cause proliferation of antigen activated T cells (clonal expansion)
3. Differentiation into effector T cells
4. Effector T cells migrate to site of infection
5. Memory T cells are developed
6. Once microbe is eliminated, infectious response dies down

Question 2

What are the two major chains of the TCR? What are the minor (a small subset) chains of the TCR?

Answer 2

Alpha and beta chains are majority of TCRs. A small subset have gamma and delta

Question 3

If a protein antigen is ingested by an APC, where does it go after that and what MHC class are they presented on?

Answer 3

They are moved into vesicles and presented on MHC class II

Question 4

What 3 components make up the TCR complex?

Answer 4

1. Alpha/beta chains of the TCR
2. Zeta Chain
3. CD3 proteins

Question 5

What is the importance of adhesion in T cell response? What are the two key proteins that mediate this response?

Answer 5

Adhesion is between a T cell and the APC, and allows for propagation of the signal.

• integrins on the T cell (especially LFA-1)
• ICAM-1 on the APC is the ligand for LFA-1

Question 6

APCs provide the antigen required for T cell activation. What else must be provided for T cell activation?

Answer 6

Costimulators

Question 7

What are the best-defined costimulators for T cells? What regulates their expression?

Answer 7

B7-1 and B7-2 expressed on APCs. APC binding of microbes increases expression of these costimulators

Question 8

What is an activating receptor on a T cell that receives the costimulatory signal from APCs?

Answer 8

CD28 receptor, expressed on T cells. Activated by B7-1 and B7-2. CD28 binding is essential for T cell activation

Question 9

What is an inhibitory receptor on a T cell that receives costimulatory signals from APCs?

Answer 9

CTLA-4 and PD-1. Both are inhibitory receptors for limiting the response of immune cells. Activated by B7-1 and B7-2.

Question 10

What is the importance of the ICOS receptor on T cells?

Answer 10

Plays a role in development and function of follicular helper T cells during germinal center responses

Question 11

What is a receptor on APCs that responds to a signal from T cells to cause increase in its function? What specifically occurs as a result?

Answer 11

CD40 receptor (on APCs) and CD40 ligand (on T cells). Binding causes APCs to express more B7 costimulators and secrete cytokines like IL-12 to enhance T cell differentiation; creates a positive feedback loop

Question 12

Why are adjuvants necessary in vaccine administration?

Answer 12

The vaccine alone (just the protein antigens) are not able to elicit T cell-dependent immune responses because of the lack of coactivation. The adjuvant is a microbial product that activates APCs and thus allows for T cell-dependent immune response

Question 13

What is the use of agents that block B7:CD28 interaction?

Answer 13

They inhibit harmful immune responses; may treat rheumatoid arthritis, graft rejection, etc.

Question 14

If a virus infects a cell and it forces the host cell to stop expressing MHC, it cannot be detected by T cells. What cell can eliminate this virally infected cell?

Answer 14

Natural killer cells.

Question 15

In T cell receptor development, what rearranges first? What follows?

Answer 15

The beta chain of TCR rearranges, which forms a pre-TCR. Rearrangement of TCR alpha follows

Question 16

What part of the TCR recognizes the antigen, and what transmits the signal?

Answer 16

The alpha/beta chain recognizes the antigen which is connected to CD3 and zeta chain which transmit the signal

Question 17

What transcription factor is present in the thymus that allows for self-antigens from the periphery to be expressed in the thymus? What disease results if this is deficient?

Answer 17

AIRE (auto-immune regulator). Mutation results in autoimmune polyendocrine syndrome

Question 18

In TCR recognition of an antigen, what are the signals that first phosphorylate CD3 and zeta proteins to cause further downstream signaling?

Answer 18

Leads to activation of tyrosine kinases (Lck and Fyn)

Question 19

What do CD3 and zeta chains signal downstream that causes pathways that regulate gene transcription?

Answer 19

ITAMs that are activated by tyrosine kinases such as Lck activate ZAP-70 which activates many downstream pathways that cause gene transcription

Question 20

How does ZAP-70 lead to the activation of NFAT, and what does this cause?

Answer 20

ZAP-70 activates PLCgamma, which cleaves PIP2 into IP3 and DAG, IP3 opens ER to release Ca2+, Ca2+ activates calcineurin, which removes phosphate from NFAT, allowing it to go to nucleus. NET result is NFAT increases expression of IL-2 and IL-2 receptor. IL-2 is required for T cell growth

Question 21

What drug inhibits calcineurin and acts as an immunosuppressant?

Answer 21

Cyclosporine and tacrolimus. Used in transplantation and in diseases of autoimmunity

Question 22

What is the key activating receptor on T cells and what is a key inhibitory receptor?

Answer 22

CD28 is the key activating receptor and CTLA-4 is the key inhibitory receptor. PD-1 is another inhibitory receptor

Question 23

What is a drug that is specific for CTLA-4 inhibition to boost immune response to tumors?

Answer 23

ipilimumab

Question 24

When a T cell encounters an antigen, its goal is to leave the lymph node and go to the site of infection. Downregulation of which molecule helps to prevent it from staying in the lymph node? What is upreguated?

Answer 24

Downregulation of L-selectin and CCR7 to prevent it from staying in the lymph nodes. Upregulation of VLA-4 (which binds to VCAM and allows for adhesion to walls of inflamed tissues)

Question 25

What small molecule regulates trafficking of T cells out of lymph nodes? What drug is an antagonist of the receptor for the molecule

Answer 25

Sphingosine 1 phosphate (and its receptor, S1P1). fingolimod is a receptor antagonist and a treatment for multiple sclerosis (treats by preventing T cells from leaving the lymph nodes and causing immune pathology)

Question 26

What are 3 critical transcription factors for increasing the expression of proteins related to T cell activation?

Answer 26

NF-kB, NFAT, and AP-1

Question 27

What is T cell exhaustion and how does it occur? What receptor activation characterizes T cell exhaustion?

Answer 27

If the T cell continues to receive signals through the TCR for a long period of time, then T cell exhaustion develops. Characterized by PD-1.

Question 28

What two cytokines in stromal cells mediates formation of memory T cells?

Answer 28

IL-7 and IL-15

Question 29

What receptor is present on phagocytes and B cells that the T helper CD4+ cells act on?

Answer 29

CD40 receptors. T cells have CD40L that bind to these receptors, thus mediating the ‘helping’ function of the T cells.