T-Cell Immunity (Activation)

Question 1

After infection and proliferation what percent of T cells will recognize the pathogen?

Answer 1

10-20%. This is part of the clonal selectio theory

Question 2

What cell brings the antigen to the LN to interact with T cells? Where do T cells enter the LN? Where to DC enter the LN?

Answer 2

Dendritic Cells

• T cells enter LN through the HEV (High Endothelial Venule)
• DC enter with antigen through the afferent lymphatic vessel

Question 3

What are the components of the TCR complex?

Answer 3

TCR alpha and beta with CD3(and greek letters) at the bottom.

TCR alpha and beta connect with the Ag from MHC and CD are responsible for transmitting the signal. The CD are homodimers

Question 4

Describe the afffinity of the TCR-MHC interaction?

Answer 4

It is low affinity.

10^-4 to 10^-5 for TCR affinity

Also low affinity are antibodies, adhesion molecules, and growthfactors.

-point is you need something else helping out (co-receptors)

Question 5

What is one of the most important co-receptors and its ligand for activating T-cells? what type of T cells?

Answer 5

CD28 (on the T-cell) binds with B7-1 or B7-2 (on the APC)

• CD28 is on CD4 cells because the interactions is with MHC II and professional APCs
• the co receptor enhances interactions between the T cells and the APC
• and the Co-receptors provides signals required for T-cell activation and differentiation

Question 6

What are the important Co-receptors and their ligand on B cells, DCs, and Macrophages (professional APCs)?

Answer 6

CD4 binds with MHC II

CD28 binds with B7-1/2

Question 7

What is the important co-receptor found on Endothelial cells, fibroblasts, macrophages, and DCs probably important for extravasation?

Answer 7

on the T-cells is LFA-1 which is a dimer of CD11a and CD18 this binds with the Ligand ICAM-1 on the APC

Question 8

What are the important receptors on activated T-cells?

Answer 8

CD25 (IL-2Ralpha) binds with IL-2 expressed on T cells

CD154 (CD40L) binds with CD40 expressed on B cells, DCs, and macrophages

Question 9

What are the important inhibitory receptors on activated T cells?

Answer 9

CTLA-4 bins with B7-1/2 expressed on B cells, DCs, and Macrophages (this competes with CD28)

PD-1 binds with PD-L1 expressed on B cells, DCs, and Macrophages

Question 11

What are the 3 steps of TCR signaling pathways?

Answer 11

1. Receptor Ligation
2. Phosphoylation of ITAMS (Immunoreceptor Tyrosine-Based Activation Motifs) by Lck (protein tyrosine kinase)
3. Recruitment and activation of ZAP-70 (protein tyrosine kinase)

Question 12

After recruitment of ZAP-70 what are the down stream pathways options?

Answer 12

1. PLC gamma -> Diacylglycerol (DAG) -> NF-kB
2. PLC gamma -> Inositol triphosphate (IP3) -> NF-AT
3. Mitogen activated protein kinases (MAPK) -> AP-1

Question 13

Describe the detailed activation of NF-kB

Answer 13

1. Ligand binding
2. Phosphoylation of ITAM by Lck
3. Recruitment and activation of ZAP-70
4. ZAP-70 activates PLC gamma –> Diacylglycerol (DAG) –> Protein Kinase C (PKC) –> which phosphorylates inhibitor of kB kinase (IkK). IkK phosphorylation and ubiquination targets it to the 26s proteasome, this allows the free NF-kB to translocate to the nucleus and transcribe genes.
   - NF-kB induces IL-2, IFN-gamma, TNF- alpha

Question 14

Describe the detailed activation of NF-AT

Answer 14

PLC gamma is activated by ZAP-70.

PLCgamma –> IP3 –>IP3receptor on the ER releasing Ca2+ from the ER into the cytoplasm.

Ca2+ causes Calmodulin to bind with Calcinuerin and activate it.

Activated Calcineurin will dephosphorylate NF-AT thus allowing it to translocate to the nucleus

NF-AT in the nucleus will induce IL-2, IL-4, IFN-gamma, ad TNF-alpha

Question 15

What is the drug that targets the NF-AT pathway and how does it work?

Answer 15

Cyclosporine and Tacrolimus target the NF-AT pathway by inhibiting the dephosphorylation of NF-AT by inhibting calcineurin

Question 16

What does the AP-1 induce?

Answer 16

IL-2

Question 17

Describe the mTOR pathway in detail?

Answer 17

PI3-K –> Akt –> mTOR –> protein translation

Question 18

What is the mTOR inhiitor?

Answer 18

Sirolimus (Rapamycin)

Question 19

In the timeline of binding, when does CTLA-4 get expressed?

Answer 19

CTLA-4 is a negative regulatior that also binds B7-1/2 competing with CD28.

-CTLA-4 is expressed after TCR ligaton

Question 20

What is the drug that inhibits CD28, how is it made, and how does it work?

Answer 20

Abatacept (co-receptor blockage)

• made by the fusion of the extracellular domain of CTLA-4 with the Fc region of IgG1
• it binds to B7-1/2 and prevents CD28 from being activated. Results in T cell anergy
• indicated in rheumatoid arthritis

Question 21

What are the three signals T cells require for activation?

Answer 21

1. TCR ligation
2. Co-receptor ligations (enhances TCR signaling such as CD28)
3. Cytokine stimulation (paracrine- from the APC, and autocrine: IL-2)

Question 22

What do the IL-Receptor family all share in common?

Answer 22

They all have a cytoplasmic gamma chain, most are dimer but IL-2 and IL-15 are timers with alpha, beta, and gamma units

Question 23

Describe the signaling pathway gamma chains deal with?

Answer 23

Gamma chains are involved with the Jak/stat pathway

1. Cytokine binds with receptor (like IL-2R) and causes di/trimerization causing autophosphorylation
2. activated JAK will recruit and phosphorylate STAT (=signal transducer and activator of transcription)
3. The phosphorlylation of STAT causes it to dimerize and translocate to the nucleus inititiation transcription

Question 24

What is Daclizumab?

Answer 24

Also known as Zenapax

• it is an IL-2 blockade, that works by blocking anti-CD25 antibody
• used in acute organ rejection

Question 25

What is Tofacitinib?

Answer 25

also known as Xeljanz and used in rheumatoid arthritis

-it is a JAK inhibitor that works by inhibitng the common gamma chain-containing cytokine receptors

Question 26

What are some factors of the extracellular response?

Answer 26

IgG and IgA (B-cells)

• complement
• neutrophils
• this would be initiated by an extracellular pathogen like bacteria

Question 27

What are some factors of the intracellular response?

Answer 27

This would be a response to intracellular pathogens like Viruses or intracellular bacteria

• leads to intracellular killing through macrophages (ROI)
• leads to cell destruction with cytotoxic CD8 T cells

Question 28

What kind of immune response do we need for fungi?

Answer 28

-fungi we need neutrophils and macrophages

Question 29

What do we need for immune resposne of helminths?

Answer 29

Helminths are parasites

-we need mast cells and IgE (B cells)

Question 30

What determines the outcome of T cell differentiation and how do T cells know what kind of immune response to mount?

Answer 30

The pathogen will dictate the outcome of T cell differentiation and the DCs will communicate to the T cells based on that pathogen what immune response to mount.

Question 31

There is an intracellular pathogen, what are the cytokines secreted by the macrophage, what T cell will respond and what are the cytokines it will produce?

Answer 31

In response to intracellular pathogen….

DC will secrete IL-12, IFN-gamma

CD4 will differentiate to Th1

Th1 will produce IFN-gamma, and TNF-alpha

Question 32

Memorize the shit out of this

Answer 32

Question 33

Tell me the important things about Memory T cells?

Answer 33

1. They are short lived
2. Found in LN and Peripheral Tissue
3. activated with low concentrations of antigen and without co-stimulation
4. upon activation they differntiate into effector cells.