T cell activation and generation of the effector T cells Flashcards
Naive T cell recirculation and activation
Naive T cells released into circulation
Move freely through circulation and enter lymph node through highly specialised blood vessels, endothelial venules
Enter lymph node, no antigen specific for TCR
Cells can migrate from lymph node to lymph node through lymphatics until they find a lymph node where there will be an antigen
If T cell then encounters antigen from an infected site, normally picked up by DC, which will travel to lymph node and enter lymph node through afferent lymphatic vessels
If the T cell that is circulating from lymph node binds the antigen, it’ll get activated, receive necessary signals by the dendritic cell and become activated T cell
Activated T cells move into circulation through thoracic duct and vena cava, and would move onto sites of infection through blood circulation
Process depends on specific chemokines released by the area of damage and inflammatory response in the tissue
If a T cell goes through second lymph node without seeing antigen it could also go back into circulation and start process of recirculation again until it finds antigen
Naive T cells are activated in secondary lymphoid organs: spleen and LNs
Naïve Lymphocyte going into LN, which has a dendritic cell that has antigen specific for the TCR.
Provides an activatory signal, now T cell is able to go back into site of damage or inflammation.
Activation of T cells happens frequently in lymph nodes
Activation of effector cells (state of functional differentiation after activation from naïve state) could also happen in periphery, areas of damage of sites of infection
What do dendritic cells detect?
What other cells can also act as APC?
They are myeloid cells that are able to detect presence of infection.
Phagocytose and present antigens in the context of MHC I and II molecules
Macrophages can also act as APC.
B cells pick up soluble antigen with B cell receptor and present it to T cells
Only activated professional APCs express high levels of MHC class II.
APCs also express co-stimulatory molecules which are essential for T cell activation.
To be fully activated and differentiated into effector or memory T cell, T cell needs 3 different signals:
Signal 1: antigen recognition
Signal 2: co-stimulation
Signal 3: cytokines
What is the first signal, antigen recognition?
The signal that initiates the immune response, so that the immune response is antigen-specific
This is because TCRs 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
In the absence of accessory molecules the T cell isn’t activated, need extra accessory molecules to succeed in inducing activation of the T cell.
What is the second signal, co stimulatory signal?
- Most commonly on dendritic cells
- But may also be on macrophages or B cells
TCR signalling is not enough to activate a naive T cell, co-stimulatory molecules are also required
- B7:CD28 - binding of B7 to cd28
- CD28 is expressed by the T cell
- B7-1 (CD80) and B7-2 (CD86) molecules are expressed by the APC
- Leads to positive co-stimulatory signalling confirming activation
- Level of expression of B7 depends on level of activity, how activated the dendritic cell is
The second signal is only provided when APC is activated
- When is no response generated?
- How is this different if APC sees a pathogen?
Co-stimulatory signals only provided by an activated DC.
- DC or APC can present peptide but will not have B7 or CD80/CD86 on its surface and unable to provide co-stimulation to CD28.
Leads onto a no response.
if it happens to be a self-peptide and there’s no co-stimulation, the T cell won’t respond. DC sees no danger, a layer of control.
- APC has seen a pathogen and has upregulated B7 molecules, can provide B7:CD28 signal to the T cell and some specific soluble molecules
- cytokines like IL-12, which will activate the T cell and make it express cytokine IL-2
- this induces proliferation and development of effector T cell.
2nd signal is only provided when APC is activated
What activates APCs?
How does this enhance T cell responses?
T cells activate APCs via CD40 – CD40L interaction, enhancing T cell responses :
T cells recognise antigen with or without B7 co-stimulators causing expression of CD40L on T cells
CD40L binds to CD40 on DC, leads to DC expression of B7 and secretion of cytokines
Activated DCs stimulate T cell proliferation and differentiation
Leads to enhanced T cell proliferation and differentiation
2nd signal: negative co-stimulatory molecules
What does negative co-stimulation inhibit?
Examples of negative co-stimulators?
Inhibits downstream effector processes initiated by TCR MHC/peptide interaction
Reduces inflammation after infection has cleared
Not expressed by naive t cells, induced upon activation
e.g
- CTLA-4, sends strong -ve signal to T cell, stops T cell from being activated, wins over CD28. Also binds to CD80 and CD86
- PD-1: programmed cell death protein 1, mainly expressed in T cells in peripheral tissue. -ve regulation of T cells
What is cytotoxic T-lymphocyte antigen 4: CTLA-4
When is it expressed?
Affinity for?
What signal does it provide to T cells?
What does it compete with?
CTLA-4 is expressed approx 2-3 days post stimulation on T cells, requires activation of T cells
Has high affinity/avidity for CD80 and CD86, but opposing effects to CD28. Wins over it because it binds in a lateral way, allowing for more B7 molecules to bind CDLTA-4
Most expressed in T cells in secondary lymphoid organs, provides negative signal to T cells
Peak levels of expression lower than CD28 but avidity of interaction is much higher
Therefore competes favourably with CD28 for ligation to CD80/86
3rd signal: cytokines, induction of T cell polarisation
What cytokines can be involved in signal 3?
- TGF-B
- IL-6
- TGF-B and IL-6
- IL-12 and IFN-y
- IL-4
Various forms of signal 3 induce differentiation of naive CD4 T cells down distinct effector pathways
Each effector T cell expresses master controller transcription factor
This transcription factor controls the expression of effector cytokines
All create environment that render T cell that’s been activated to carry out different function
Signal 3 is delivered by APC, leading onto signals that make the T cell become a particular type of functional T cell
What master controller transcription factor does each effector T cell express?
T reg cells: TGF-B induces activation in T cell, leading onto T reg cells. Mediated by master transcription factor FoxP3
T follicular helper cell: IL-6 induces activation with master TF Bcl6
Th17 cell: TGF-B and IL-6 with master RORyT
Th1 cell: IL-12 and IFN-y with master T-bet
Th2 cell: IL-4 with master GATA3
T cell could also produce autocrine factors like IL-2
What is IL-2 important for?
IL-2 important to sustain T cell activation and proliferation, without it T cells can’t proliferate
T cell produce lots of IL-2, provides autocrine signal to T cell to allow proliferation
Regulatory T cells that differentiate in thymus have high levels of IL-2 receptors
Sequesters IL-2, blocking the process – regulation
IL-2 is a master cytokine required to sustain proliferation of T cells upon activation
- maintains functional regulatory t cells
- sustains proliferation and differentiation - effector and memory T cells
In process of activation T cells express different receptors and the time of expression is important
What surface molecules do they express?
After activation, T cells express CD69, important to retain them in lymph node long enough to be fully activated and receive all signals.
Once they downregulate CD69 they go out of the lymph node and into circulation, to sites of infection.
Then CD25 follows, receptor for IL-2, important for proliferation
CD40L follows, can provide activation of dendritic cells, macrophages, B cells
Later stage, CTLA-4 which can calm response or control it.
What are the consequences of this interaction?
Naive T cells can differentiate into effector cells - cells that carry out its function
Can be CD4+ T cell - activates macrophages and B cells to induce antibody production and inflammatory cells depending on type of polaring phenotype
Or go into memory pool, memory CD4+ T cells
CD8s become effector CD8+ T cells - cytotoxic T cells that kill virally infected cells
or become memory CD8+ T cells
CD4 subsets have different functions
What effector cytokines does Treg produce and their functions?
Treg:
Polarising cytokines: IL-2, TGF-B
Master TF: FOXP3
IL-10, TGF-B
effector functions: regulation, suppresion of immune and inflammatory responses
Function of T helper 2 cells
TH2 cells produce IL-4,IL-5, IL-13, effector cytokines that help eliminate extracellular parasitic infections such as worms
Promote class switching to IgE which causes inflammatory cytokines to be released by eosinophils and mast cells
Also increase intestinal movement and mucus production
IgE also mediates allergy
