Lecture 6 - Activation of T cells Flashcards
What is the anatomy of a T cell immune response?
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
what are some of the challenges facing the immune system during a response?
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
Why is peptide alone not enough to activate T cell?
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
What does activation T cell require?
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
What happens if a T cell only recieves signal 1 (binding of TCR to peptide/MHC complex)?
T cell will become Anergic = complete unresposiveness of a T cell to its antigen
What happens if T cell only recieves signal 1, then recieves both signal 1 and 2, and what is the benefit of this?
Initial recieveing of only signal one made the T cell anergic, if recieves both no response, STOPS AUTOREACTIVITY
How does 2 signal mechanism control activation of naive T cells?
because ONLY APC can express costimulatory molecules CD80 and CD86 and expression of these molecules is controlled by inflammation
How is expression of CD80 and CD86 costimulatory molecules on APCs controlled by inflammation?
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
How does provision of signal 1 and 2 activation niave T cell
initiates construction of immunological synapsse complex (capping)
What is the process of capping following the provision of signal 1 and 2?
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’
What is the purpose of the immunological synapse [central ‘cap’]?
- 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
What does the immunological synapse do?
brings together molecules that initiate T cell receptor signalling whilst excluding molecules that can prevent signalling
How do kinases interact with signal 1 and 2 to activate T cell?
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
What does IL-2 do?
cytokine required for the growth and survival of all niave T cells
-normally secreted by T cells can be secreted by dendritic cells
How is IL-2 involved in T cell proliferation?
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
How has helicobacter pylori evolved to prevent T cell activation?
Helicobacter pylori - produces gastric ulcers
-can stop transcription and production of T cell growth factor IL-2
How has HIV evolved to prevent T cell activation?
HIV
- prevents efficient phosphorylation of key molecules in T cell receptor signal cascade
- prevent formation of immunological synapse
What are ‘runners’?
molecules that tell cells to activate and enable them to migrate to site of infection e.g. inflammatory signals - interferons, chemokines
How can the immune system manipulate antigen processing to enable fast delivery of peptides to MHC molecules?
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
Though what pathway does MHCI present peptides?
MHCI presents peptides through the ENDOGENOUS PATHWAYS
Through what pathway does MHCII present peptides?
MHCII presents peptides through exogenous pathway
What transport protein transports peptide fragments from proteasome to the ER?
TAP1 and TAP2 complex
How are peptides more rapidly produced during an immune response?
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
How can the peptide/MHC complex be made more stable during an immune response?
Interferons cause upregulation of TAP1 and TAP2 results in
- peptides with a greater affinity for MHC
- stabilisation of peptide/MHC complex at cell surface
What happens if T cells are not switched off?
Massive destruction of host tissue
When does switching off of T cells occur?
following signalling through negative costimulatory molecules
What are the most common negative costimulatory molecules for T cells?
1) cytotoxic lymphocyte antigen (CTLA-4) <-muation typical in diabetes
2) programmed death domain (PD-1)
Upregulated when threat destroyed
How does signalling with CTLA-4 result in T cell signalling being switched off?
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
How does signalling with PD-1 result in T cell signalling being switched off?
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
What molecules act as costimulatory signals for B cell activation?
CD19, CD21, CD81 as lead to kinase activation and proliferation
What is the negative costimulatory signal for B cell turning off?
the Fc receptor FcyRIIB leads to dephosphorylation of key molecules for B cell activation
