Lecture 6 - Activation of T cells

Question 1

What is the anatomy of a T cell immune response?

Answer 1

1) entry of a pathogen and innate immune response
2) dendrtitic cell transports antigen into the lymph node via migration in the lymphatic vessel network
3) presents antigen to niave T cell which stimulated expansion and differentiation of ‘primed’ effector T cell
4) T cell migrates back to the site of infection to destroy pathogen

Question 2

what are some of the challenges facing the immune system during a response?

Answer 2

1) Detect pathogen
2) Recruit approriate immune cell to deal with pathogen
3) activate the immune cell to respond to the pathogen
4) hone the immune response to be most appropraite to deal with pathogen
5) direct acivated immune cell to where threat is
6) switch off immune response when threat is removed

Question 3

Why is peptide alone not enough to activate T cell?

Answer 3

Any nucleated cell can express MHCI molecules, present mostly own peptides on surface. If T cell acitvation only required peptides T cell would destroy own tissues
ALSO negative selection not 100% efficient, 5-10% T cells are capapble of reponding to own tissues

Question 4

What does activation T cell require?

Answer 4

Two signals:

1) binding of TCR to peptide/MHC complex
2) binding of CD28 on T cells to costimulatory molecules CD80 or CD86 on APC

Question 5

What happens if a T cell only recieves signal 1 (binding of TCR to peptide/MHC complex)?

Answer 5

T cell will become Anergic = complete unresposiveness of a T cell to its antigen

Question 6

What happens if T cell only recieves signal 1, then recieves both signal 1 and 2, and what is the benefit of this?

Answer 6

Initial recieveing of only signal one made the T cell anergic, if recieves both no response, STOPS AUTOREACTIVITY

Question 7

How does 2 signal mechanism control activation of naive T cells?

Answer 7

because ONLY APC can express costimulatory molecules CD80 and CD86 and expression of these molecules is controlled by inflammation

Question 8

How is expression of CD80 and CD86 costimulatory molecules on APCs controlled by inflammation?

Answer 8

1) In non inflamed state, APC has low levels of MHC on surface and low levels of CD80/CD86 - number determines the strength of signal must have enough to pass threshhold level
2) During infection APC recieves signal to increase number of MHC and costimulatory molecules on its surface
3) Niave T cells require 3rd signal which induces differentiation what kind of immune response needs to differentiate into

Question 9

How does provision of signal 1 and 2 activation niave T cell

Answer 9

initiates construction of immunological synapsse complex (capping)

Question 10

What is the process of capping following the provision of signal 1 and 2?

Answer 10

1) APC is activated
2) results in reoganisation of cytoskeleton resulting in key molecules being concentrated in one area to produce tight junction = immunological synapse = central ‘cap’

Question 11

What is the purpose of the immunological synapse [central ‘cap’]?

Answer 11

• to increase the strength of interaction of MHC/peptide and APC to activate all components needed for effective immune response
• allows a longer time for response more tightly held together
• recruit kinases to the cytoplasmic tail of the TCR

Question 12

What does the immunological synapse do?

Answer 12

brings together molecules that initiate T cell receptor signalling whilst excluding molecules that can prevent signalling

Question 13

How do kinases interact with signal 1 and 2 to activate T cell?

Answer 13

Signal 1
-CD3 complex comtains immunoreceptor tyrosine based activation motifs (ITAM’s) get phosphorylated by kinases triggers a biochemical cascade
Signal 2
-phosphorylation of CD28 amplifies the TCR signal

Question 14

What does IL-2 do?

Answer 14

cytokine required for the growth and survival of all niave T cells
-normally secreted by T cells can be secreted by dendritic cells

Question 15

How is IL-2 involved in T cell proliferation?

Answer 15

1) niave T cells have low affinity IL-2 receptors on surface
2) when IL-2 produced forms high affinity receptor which allows cells to absorb IL-2 from surroundings
3) cell proliferates

Question 16

How has helicobacter pylori evolved to prevent T cell activation?

Answer 16

Helicobacter pylori - produces gastric ulcers

-can stop transcription and production of T cell growth factor IL-2

Question 17

How has HIV evolved to prevent T cell activation?

Answer 17

HIV

• prevents efficient phosphorylation of key molecules in T cell receptor signal cascade
• prevent formation of immunological synapse

Question 18

What are ‘runners’?

Answer 18

molecules that tell cells to activate and enable them to migrate to site of infection e.g. inflammatory signals - interferons, chemokines

Question 19

How can the immune system manipulate antigen processing to enable fast delivery of peptides to MHC molecules?

Answer 19

Two principles:

1) Rapid production of peptides
2) Stabilisation of peptide-MHC complex at cell surface, leading to a more efficient interaction between APC and T cell

Question 20

Though what pathway does MHCI present peptides?

Answer 20

MHCI presents peptides through the ENDOGENOUS PATHWAYS

Question 21

Through what pathway does MHCII present peptides?

Answer 21

MHCII presents peptides through exogenous pathway

Question 22

What transport protein transports peptide fragments from proteasome to the ER?

Answer 22

TAP1 and TAP2 complex

Question 23

How are peptides more rapidly produced during an immune response?

Answer 23

Interferons produced by immune system in response to viral attack manipulate endogenous antigen processing apthway

• open up the proteasome cylinder to increase rate of protein entry and peptide release
• known as a immunoproteasome = highly efficient at generating peptides

Question 24

How can the peptide/MHC complex be made more stable during an immune response?

Answer 24

Interferons cause upregulation of TAP1 and TAP2 results in

• peptides with a greater affinity for MHC
• stabilisation of peptide/MHC complex at cell surface

Question 25

What happens if T cells are not switched off?

Answer 25

Massive destruction of host tissue

Question 26

When does switching off of T cells occur?

Answer 26

following signalling through negative costimulatory molecules

Question 27

What are the most common negative costimulatory molecules for T cells?

Answer 27

1) cytotoxic lymphocyte antigen (CTLA-4) <-muation typical in diabetes
2) programmed death domain (PD-1)
Upregulated when threat destroyed

Question 28

How does signalling with CTLA-4 result in T cell signalling being switched off?

Answer 28

1) cytoplasmic tail of CTLA-4 has immunoreceptor tyrosine-based inhibitory motif (ITIM)
2) ITIM activation by binding of CTLA-4 to CD80/CD86 on APC
3) ITIM activation recruits phosphotases to receptor complex
4) phosphotases de-phosphorylate key molecule in T cell activation

Question 29

How does signalling with PD-1 result in T cell signalling being switched off?

Answer 29

1) PD-1 on T cell comes into contact with PDL-2 on APC OR PDL-1 on peripheral tissue
2) PD-1 has cytoplasmic ITIM and can phosphorylate key molecules for T cell activation
3) T cell signalling turned off

Question 30

What molecules act as costimulatory signals for B cell activation?

Answer 30

CD19, CD21, CD81 as lead to kinase activation and proliferation

Question 31

What is the negative costimulatory signal for B cell turning off?

Answer 31

the Fc receptor FcyRIIB leads to dephosphorylation of key molecules for B cell activation