T Cell Activation Flashcards
How do naive T cells circulate and then get activated?
They are released into circulation and can enter a lymph node through highly specialised blood vessels called high endothelial venules
Then they enter and there is no antigen specific for the T-cell receptor cells can migrate from lymph node to lymph node until they find a lymph node where there will be an antigen
Some of the T cells may join this lymph node
If a T cell encounters antigen, which would normally come from a infection site, picked up by a dendritic cell which will travel and enter the lymph node through the afferent lymphatic vessels
If the T cell binds the antigen it will get activated, they will receive the necessary signals from the dendritic cell and become an activated T cell
Activate dT cells move into the circulation through the thoracic duct in the vena cava and would preferentially move onto the sites of infection through blood circulation
- This process depends on specific chemokines released by inflammatory response
If a T cell goes through the second lymph node without seeing an antigen it can also go back to the circulation and start the process of recirculation again until it finds an antigen
What 3 signals do T cells need to differentiate?
To be fully activated and differentiated into effector or memory T cell, the T cell needs 3 different signals:
- Signal 1: Antigen recognition - Signal 2: Co-stimulation - Signal 3: Cytokines – Part 3
How does antigen recognition bind to TCR?
Is the signal that initiates the immune response, so that the immune response is antigen-specific
TCR in T cell recognises the antigen in the context of MHC:
- CD4 TCR recognises MHC II/peptide complex
- CD8 TCR recognises MHC I/peptide complex
But in the T cell – APC interaction other molecules participate…
How do co-stimulatory molecules activate T cells?
1) B7:CD28
- CD28 is expressed by the T cell
- B7-1 (CD80) and B7-2 (CD86) molecules are expressed by the APC
- The level of B7 on a dendritic cell depends on how activated a dendritic cell is
If there is no co stimulator then there is no T cell response
If an APC has seen a pathogen and has upregulated B7 molecules and also some cytokines which will then activate the T cell and make it express an autocrine cytokine called IL-2
This will induce proliferation and the development of an effector cell, the T cell that is going to go an carry out its effector function
What signals do T cells provide to APCs?
T cells activate APCs via CD40 – CD40L interaction, enhancing T cell responses.
Upon activation, T cells upregulate CD40L, which binds to CD40 on DCs and stimulates the production of co-stimulatory molecules and cytokines by the DCs, thus enhancing T cell proliferation and differentiation.
What do negative costimulatory molecules do?
They inhibit the downstream effector processes initiated by TCR MHC/peptide interaction
Reduce inflammation after the infection has cleared
Not expressed by naïve T cells, there are induced upon activation
For example
- CTLA-4 and PD-1, LAG3
- CTLA-4 sends a very strong and predominant signal to the T cell, overriding CD28
- PD-1: Programmed cell death protein 1.
- Mainly expressed in T cells in peripheral tissues.
When is CTLA-4 expressed?
CTLA-4 is expressed approx. 2-3 days post stimulation
It has high affinity/avidity for CD80 but opposing effects to CD28.
It is mostly expressed in T cells in secondary lymphoid organs.
Peak levels of expression lower than CD28 but avidity of interaction is much higher
Therefore, competes favourably with CD28 for ligation to CD80/86
How do cytokines act as signals for T cell differentiation?
Various forms of signal 3 induce the differentiation of naive CD4 T cells down distinct effector pathways.
Each effector T cells expresses a master controller transcription factor
This transcription factor controls the expression of effector cytokines
Different homing patterns, different chemokine receptors and adhesion molecules direct them to different sites.
For example TGF-beta will induce activation of a T cell leading it on a regulatory phenotype mediated by FoxP3
TFH cells activates in the presence of IL-6 mediated
The presence of TGF-beta and IL-6 causes activation into TH17 cells mediated by RORgammaT
IL-12 and IFN-gamma causes TH1 cells mediated by T-bet
IL-4 causes activation into TH2 cells mediated by GATA3
What does IL-2 do?
IL-2 is a growth, survival and differentiation factor for T cells and Tregs.
After activation by dendritic cells the T cell will start producing a lot of IL-2, providing an autocrine T cells for proliferation
Regulatory T cells have a higher levels of a receptor for IL-2 and they can sequester IL-2, blocking that process
What different surface molecules do T cells express throughout differentiation?
In the process of activation T cell express different receptors
After activation, T cells express CD69 which is important to retain them in the lymph node long enough for them to be fully activated and receive all the signals
Then CD25; a receptor for IL-2 so important in proliferation
Then CD40L which can provide extra signals to dendritic cells
Finally CTLA-4, hours or days after, which can calm the response
What happens after T cells differentiate?
It can become an effector CD4+ T cell which can activate macrophages, B cells and other cells as well as inflammatory cells
Or could go into the memory pool
If it is a CD8+ cell and it is an effector is can kill the infected cells and activate macrophages
Or become a memory cell
What happens following successful TCR signalling?
Following successful signalling via the TCR, a naive T cell will:
1. Modify the expression of surface molecules 2. Upregulate cytokine production 3. Undergo active rounds of proliferation - Upregulate expression of pro-survival genes - Upregulate expression of IL-2 and IL-2R-a 4. Differentiate into effector or memory cells
What induces T cell polarisation into different subsets?
The polarising cytokines
These are generated by the stimulating APC
Which cytokines they produce depends on:
- The cellular origin of the APC
- The maturation and activation status of the APC
- Which pathogens or inflammatory mediators were encountered by the APC
- In which tissue environment the encounter takes place
What does each subset of CD4+ T cells do?
A number of different CD4 helper subsets have been identified with different functions
TH1 cells, upon full differentiation, will activate macrophages to enhance the ability to destroy intracellular pathogens
- Then they can kill the pathogen which is mediated by the release of IFN-gamma
TH2 cells can produce IL-4, 5 and 13 and recruit cells that are important for anti-parasitic responses ad also support the production of antibodies by plasma cells
TH17 cells could act on specific tissue cells and lead onto the recruitment of neutrophils; a particularly good antibacterial response
TFH cells will provide signals to the B cells to differentiate and produce antibodies
Regulatory T cells could actually alter the phenotype of an immature dendritic cell rendering it unable to activate a T cell
How are TH1 cells activated and their functions?
These were the first identified subsets
TH1 polarisation occurs in response to the presence of intracellular pathogens such as viruses and bacteria that are ingested by and destroyed by phagocytes.
Master transcription factor that controls differentiation – T-bet
IFN-gamma can amplify TH1 differentiation
Function:
They produce IFNg
Help to activate macrophages to ingest and destroy microbes
Binds to B cells to induce antibody class switching to IgG (opsonization).
All helpful response in eliminating an intracellular pathogen
