T cell activation via a messenger Flashcards
What is the messenger that activates a T cell?
Dendritic cell: the key antigen presenting cells. They deliver 3 signals
1) Peptide/MCH
2) These have co-stimulatory molecules which help activate the naive T cell.
3) Dendritic cell secrete IL6, IL12 to T cells to determine their differentiation.
What is the messenger that activates a T cell?
Dendritic cell: the key antigen presenting cells.
These have co-stimulatory molecules which help activate the naive T cell.
Dendritic cell secrete IL6, IL12 to T cells
What receptor recognises PAMPs (of microbes) on Naive Dendritic cells?
Toll-like receptors.
Activation turns on a kinase cascade and Transcription factors (IRNs) which cause the up-regulation of co-stimulatory molecules on dendritic surface.
This drives maturation of DC.
What is DC maturation>
The transformation from antigen capturing antigen to a cell that present antigen to engage the T cells.
Lots of different processes that are needed at lots of different times.
Describe an experiment which
Grown DC cells from bone marrow of mouse.
When they sense microbial product they increase their capture of material from the surrounding environment.
Add LPS, toll like receptor ligand, the activity increases. Cells membrane ruffling and cells fill up with endosome due to large amount of pathogen antigen endocytosis into the cell.
Antigen and LPS at the same time causes more T cells activation compared to Antigen added before LPS.
Measures IL-2 production by T cells; more cytokine, more T cell stimulation.
What are the different ways DC can take up antigens
To be presented to CD4+ on MCH2
1) Macropinocytosis
3) Receptor-mediated endocytosis
To be presented on CD8+ on MHC1
3) virus infection
What are the different ways DC can take up antigens
To be presented to CD4+ on MCH2
1) Macropinocytosis
3) Receptor-mediated endocytosis
To be presented on CD8+ on MHC1
3) virus infection in DC cell
How is the innate detection system vulnerable?
Viruses may evade dendritic cells and CD8+ T cell are not made.
What is cross presentation?
The presentation of exogenous antigens, to get into cytosol by a endocytic pathway, and loaded on to MHC1 instead of the normal MHC2.
What receptor recognises PAMPs (of microbes) on Naive Dendritic cells?
Toll-like receptors.
Toll receptors sense inside and outside the cell
Activation turns on a kinase cascade and Transcription factors which cause the up-regulation of co-stimulatory molecules on dendritic surface; it drives DC maturation.
Give examples of Toll-like receptors and whether they are outside or inside the DC cell.
On outside:
- TLR4: which recognises LPS
- TLR1/2: sense other bacterial antigens
On inside: TLR3: which recognises nucleic acid signatures unique to pathogens within the endosome.
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Describe what happens to a DC after binding to pathogen via TLR
1) Increases antigen capture
2) Increases MHC production so more translocate to DC surface
3) Increases co-stimulatory molecule production
4) Increase cytokine production (IL6, IL12)
5) Increases expression of CCR7 a chemokine receptor
What are some co-stimulatory molecules?
- CD80
- CD86
- CD40
What does receptor CCR7 expression on DC surface lead to? Why is it important?
This is important for the DC to be guided to lymphoid tissues by following a gradient of chemokines called CCL21.
No CCR7 receptor means the DC cannot move out of tissues.
What does receptor CCR7 expression on DC surface lead to? Why is it important?
This is important for the DC to be guided to lymphoid tissues by following a gradient of chemokines called CCL21.
No CCR7 receptor means the DC cannot move out of tissues to lymph nodes to stimulate T cells.
Describe how T cells enter the lymph nodes.
Lymph nodes are interconnected; upstream and downstream.
There are two sources of T cells: cells from blood or cells from upstream afferent lymph nodes enter a lymph node across the high endothelial venules (HEV) in the cortex; they then look for specific antigen which is very rare to find its match.
If not in one lymph node, antigen may be in next lymph node.
What is the role of adhesion molecules?
1) T cell Binds to DC via LFA-1 on T cell and ICAM-1 on DC. This is weak affinity.
2) The binding of the TCR and MHC signals to LFA-1 on T cell to change conformation. This is called inside out signalling.
3) Conformational change increases affinity for DC ICAM-1 and prolongs cell contact. This is strong binding
What strengthens adhesion binding?
The T cell TCR binding to MHC-peptide complex.
What increases expression of B7 molecules on DC cells? What does it bind to?
Activated Toll like receptor signalling receptor on DC.
B7 binds to CD28 on naive T cell.
How do co-stimulators (DC signal 2) link innate and adaptive immune system?
It is regulated by pathogen signals
How does T cell differentiation work?
Cytokine environment in lymph node cytokine environment is important for turning on different transcription factors in T cell to differentiate activate production of other cytokines that effect other cells as a helper or a killer.
For example, cytokine TGF-beta from DC, activates T cell to become regulatory T cell and acivates its TF called FoxP3 which causes cyokines TGF, IL10 to be made by the T cell.
What do mature Th1 cells do once activated by an immature effect T cell?
Th1 release IL2, IFN which effects macrophages, B cell activation, oposizing antibodies
What do mature Th2 cells do once activated by an immature effect T cell?
Th2 release IL4, IL5 which activate B cells to make antibodies
What is the pathway that leads to B cell/ antibody activation?
DC activate naive cells in T cell zone of lymph nodes via antigen.
B cells from blood that are activated with the same antigen present to helper T cell in the T cell zone.
They form conjugates with specific T cells
What happens if there is no signal 2; there is no co-stimulation?
T cell becomes anergic. T cell is not stimulated.
Tolerance: if DC has not upregulated co-stimulatory molecule, T cell become unresponsive
How do vaccines relate to co-stimulatory molecules? What are adjuvants?
Vaccines have to induce co-stimulatory signal through the use of ADJUVANTS as well as MHC-peptide antigenic component in order to activate T cells.
Adjuvants induce signal 2.
What happens if there is no signal 2; there is no co-stimulation?
T cell becomes anergic. T cell is not stimulated.
Anergy is a form of Tolerance: if DC has not upregulated co-stimulatory molecule, T cell become unresponsive as this not the correct binding is was educated to recognise.
How do vaccines relate to co-stimulatory molecules? What are adjuvants?
Vaccines have to induce co-stimulatory signal through the use of ADJUVANTS as well as MHC-peptide antigenic component in order to activate T cells.
Adjuvants induce signal 2.and cells become anergic/unresponsive.
What is an example of a good adjuvants?
Heat-killed microbes
What are the two stages of the adaptive immune response?
Stage 1: DC activate naive T cells to proliferate and differentiate into effector cells.
Stage 2: T cells carry out effector function
What are some effector functions of CD8+ and CD4+ AFTER DC activation?
CD8+ will travel to site of infection and cells die via apoptosis; Th1 CD4+ travel to site of infection to activate macrophage to kill; Th2 CD4+ interact with specific B cells in lymphoid tissue to make antibodies.
What is one strategy to eradicate tumours?
Tumours don’t express co-stimulatory molecules so T cells are not activated.
-Grown cancer patients blood DC in vitro, incubate with tumour material, and reinfuse to attempt to re-stimulate CD8+ killing response.
What does alloreactive T cells refer to in terms of acute direct recognition?
T cells that are not educates/tolerised to the new peptides from new graft transplant. Graph cell presents its foreign antigen. T cells destroy organ/graft.
How does matching transplant organ to blood type help slow rejection in terms of indirect allorecognition pathway.
Indirect pathway of rejection via APC recognition of DEAD graph cell with its MHC variants/allotyoes containing graph protein antigen. APC cell takes up which are displayed by its own MHC molecules as a processed foreign antigen.
What are anti-HLA antibodies in terms of indirect allorecognition pathway?
Host B cell (APC) can take up graph MHC as it looks forign. B cell processes and presents, receives help from T cell which allows it to become a plasma cell and produce HLA-antibody?
What are anti-HLA antibodies in terms of indirect allorecognition pathway?
Host B cell (APC) can take up graph MHC as it looks forign. B cell processes and presents, receives help from PHYSICALLY LINKED T cell which allows it to become a plasma cell and produce HLA-antibody that attack graph MHC molecules.
