T Cell Immunity

Question 1

How are the T cells activated

Answer 1

They are activated by TCR, coreceptors (that bind to ligands) and cytokines

Question 2

How are Naive T cells activated

Answer 2

1. They move from lymph node to lymph node via blood 2. In the lymph node they look for dendritic cells, they literally crawl over a dendritic cell and see if it is presenting an antigen 3. If an antigen is presented the T cell binds to the antigen and this leads to clonal expansion

Question 3

What T cells does the dendritic cells stimulate and what happens to the T cells next

Answer 3

1. Stimulate both CD4 and CD8 T cells 2. They undergo proliferation and differentiation 3. T cells exit the lymph node through the blood stream and go to the site of infection

Question 4

How does TCR lead to development of a signal cascade after it binds to an antigen

Answer 4

It has accessory molecules associated with which are a dimer of CD3epsiolon-gamma and CD3epsiolon-delta and a homodimer of zeta chain. The TCR itself has a very short intramembrane domain so it cannot lead to singal cascade by itself.

The zeta chain are actually the ones that do the work for signal cascade

Question 5

Explain the mechanism of action in detail for T cell activation

Answer 5

When a dendritic cell presents an antigen to a T cell, the T cell remains bound to the dendritic cell for a long period of time. However, it is known that the affinity TCR with antigen on MHC is very low and it alone cannot account for the binding of the two cells. Other molecules that are involved here are:

1. CD4 or CD8 proteins also bind to the MHC increasing its affinity
2. Coreceptors come in to play here, the most common one being CD28 that binds to B7-1/2 (aka CD80/CD86)
3. The greatest increase in affinity comes from ICAM-1s expressed on denritic cells that bind with LFA-1s expressed on T cells

Question 6

What are some of the important co receptors and what are their properties

Answer 6

1. CD4, they bind to MHC class II only, MHC class II are present on APCs which are B cells, macrophages and dendritic cells
2. CD8, binds to MHC I, present in all nucleated cells
3. CD28, binds to B7-1/2, presented by APCs: macrophages, dendritic cells and B cells
4. LFA-1, binds to ICAM-1, presented by Endothelial, fibroblast, macrophages and dendritic cells

Question 7

What is LFA-1 made of

Answer 7

It is a dimer of CD11a and CD18

Question 8

What are some of the other receptors we should know about

Answer 8

1. CD25, it is part of the IL-2 ligands so it binds with IL-2. It is expressed by all T cells
2. CD154, it is also called CD40L so it binds to CD40. It is expressed by APCs:macrophages, denritic cells and B cells

Question 9

Immunological check points

Answer 9

Question 10

Explain the TCR signaling pathway

Answer 10

1. TCR ligation
2. Phosphorylation of ITAMs by Lck = Immunological Tyrosine-based Activation Motifs AND Lymphocyte specific protein tyrosine Kinase
3. Recruitment and activation of ZAP70 binding to the zeta chains
4. Phospholipase C gamma (PLCgamma) makes DAG and IP3.
5. DAG activates NFkappaB and IP3 activates NF-AT
6. ZAP70 also leads to MAPK activation leading to AP-1 activation

Question 11

NFkappaB

Answer 11

Question 12

NF-AT

Answer 12

When NF-AT is p’s it stays in the cytoplasm, when it is dep’s it is activated and goes into the nucleus.

1. PLC makes IP3
2. IP3 bind to IP3 receptors on ER and released Ca
3. Ca binds to calmodulin that activates an enzyme called Calcineurin which catalyzes the dep’s of NF-AT to activate it.

IMPORTANT: 2 drugs that inhibit Calcineurin are Cyclosporin and Tacrolimus. They are used in transplants.

Question 13

What are induced by the 3 pathways of T cells

Answer 13

1. NFkappaB induces formation of IL-2, IFNgamma and TNFalpha
2. NF-AT induces formation of IL-2, IL-4, IFNgamma and TNFalpha
3. AP-1 induces formation of IL-2

Question 14

What is another pathway that is not well understood but important in T cell mediated immune response

Answer 14

The mTOR pathway:

1. PI3-K activates Akt
2. Akt activates(?) mTOR
3. mTOR increases protein translation

Siromilus (rapamycin) inhibits mTOR and doesnt allow the cell to advance from G1 phase

Question 15

What is the cytokine that is required for T cell activation

Answer 15

CD-12

Question 16

What are the drugs that can regulate immunologic checkpoints

Answer 16

1. Ipillimumab
2. Nivolumab
3. Abatacept is a drug that is a CTLA4-Ig fused together. It binds to CTLA4 and turns off the T cells. This drug is used in autoimmune diseases such as reuhmatoid arthritis.

Question 17

Where does the cytokine come from for T cell activation

Answer 17

Paracrine - APC and autocrine - IL2

Question 18

What is the structure of IL-2

Answer 18

It is a trimer, it consists of an alpha chain, beta chain and a common gamma chain (this common gamma chain is shared by an entire class of cytokines).

IL2Ralpha is also called CD25.

Question 19

What is the signaling pathway shared by this family of cytokines

Answer 19

JAK-STAT pathway

Question 20

Drugs that inhibit this pathway and their uses

Answer 20

1. Daclizumba (Zenapax) - blocks CD25, it is an antibody, acute organ rejection
2. Tofacitinib (Xeljanz) - JAK inhibitor, rhematoid arthritis, inhibits common gamma chain pathways

Question 21

What kind of specific response is required for different pathogens

Answer 21

1. Extracellular bacteria: IgA, IgG, complement and neutrophils
2. Intracellular pathogens (virus and bacteria): Intercellular killing, macrophages, CD8 Cells
3. Fungi: neutrophils and macrophages
4. Helminths: Mast cells and IgE (B cells)

Question 22

These are the different classes of CD4 cells. It is important to know that we cant have a fine distinction in the immune response for different pathogens and often an adaptive immune response organized by CD4 cells is a combination of several differently classified immune response that are shown in the diagram

Answer 22

This is what the CD4 T cells differentiate into.

The folicular helper T cells dont make any cytokines but rather they go to the lymph nodes and aid in B cells activation and function in adaptive immune response

Question 23

How does the CD4 T cells know what to differentiate into

Answer 23

They take orders from dendritic cells which in turn get the required signals from PAMPs. So really the pathogen itself drives the specific immune response

Question 24

Describe the properties of Memory T cells

Answer 24

1. They’re the only T cells that remain after the pathogen has been completely removed
2. They’re found in the lymph nodes and in the peripheral tissues, they wander around doing whatever they want to do
3. They get activated when they encounter the same pathogen, they DO NOT NEED COSTIMULATION.
4. Upon activation they themselves differentiate into effector T cells