L5 - Lymphocyte activation: T cells Flashcards
What are the types of effector T cells?
Cytotoxic T cells (CD8+) – kill infected cells
Helper T cells (CD4+) – secrete cytokines
What are naive/virgin T cells?
Haven’t seen any antigens yet
What happens to naive/virgin T cells once they exit the thymus?
Recirculate via blood/lympathics through secondary lymphoid tissue (lymph nodes & spleen)
Contact with specific Ag & APC leads to clonal proliferation & differentiation
What happens in the lymphoid tissue?
T cells recognise Ag/MHC antigen on APCs
Array of APC are found, some specialised, trap & present Ag (in lymph nodes & spleen)
T cell effectors then migrate to sites of infection
How do naive/virgin T cells survive?
Naïve T cells must encounter Ag for survival
How do T cells get to where they need to be?
Enter lymph node from blood via high endothelial venules (HEV)
T cell area rich in dendritic cells & macrophages (APCs)
APC present specific antigen & deliver other activation signals (eg. cytokines)
T cells can then proliferate & leave as activated T cells – they know where to go
What happens to T cells that don’t become activated?
T cells that are not activated leave lymph node via cortical sinuses into the lymphatics
Re-enter circulation – recycled for another day
What are cell adhesion molecules (CAM)?
Molecules expressed on surface of T cells, bind ligands expressed on other cells
Different molecular sets mediate different interactions
– Naïve T cell with HEV
– T cell with APC
– Effector T cell & target cell
T cell contact with APC
- T cells contact APCs using CAMs
- TCR scans APC peptide/MHC complexes
– No recognition = disengages
– Recognition = signal from TCR complex (CD3)
What happens in TCR recognises MHC complex on APC?
1) Signal from TCR complex (CD3)
2) Increases affinity of CAM interactions
3) T cell divides
4) Progeny differentiate to effector cells
5) T cell-mediated response
TCR affinity for MHC is very low - what does this mean?
The chances of the T cell hanging around are really low due to the poor affinity
T cell has to rely on other molecules to hold it to the APC
How is the TCR held to the MHC molecule?
CD4 is on the T cell & interacts with MHC II – acts as Sellotape holding the cells together while the TCR scans the molecule
If the TCR recognises the peptide, it sends a signal & LFA-1 & ICAM-1 change in structure
Changes the affinity of them for each other to anchor the 2 cells together for long enough for the T cell to become activated
What is LFA-1?
Leukocyte function-associated antigen (integrin)
What is ICAM-1?
Intracellular adhesion molecule
Co-stimulation of T cells
Need 3 signals to become an effector cell - fail safe mechanism
Signal 1
Signal 2
Signal 3
Co-stimulation of T cells
SIGNAL 1
Naïve T cells receive a signal from TCR containing MHC/peptide on APC
Involved CD3 & zeta
Co-stimulation of T cells
SIGNAL 2
Professional APC also express co-stimulatory molecules (B7.1 & B7.2) that bind CD28 expressed by naïve T cells & delivers signal 2 to the T cell
B7.1 is also called CD80
B7.2 is also called CD86
Co-stimulation of T cells
SIGNAL 3
APC also release cytokines which bind cytokine receptors now upregulated on naïve T cells which deliver signal 3
What happens once the T cell is activated by all 3 signals?
Activated T cells express ICOS & CTLA-4
What does ICOS do?
ICOS (related to CD28) binds ICOSL on APC to induce cytokine secretion by T cells
What does CTLA-4 do?
CTLA-4 is highly related to CD28, & shows stronger binding to B7 than CD28
Binding of CTLA-4 to B7 on APC delivers a negative signal to activated T cell – acts as an antagonist to CD28 & serves to dampen down the T cell response
Importance of CTLA-4
A protein receptor that functions as an immune checkpoint and down-regulates immune responses
Once T cells are triggered, there are other T cells that need shutting down – don’t want to keep triggering cells
Without it you get autoimmune diseases
Cancer treatment & CTLA-4
Treatment of cancer patients with anti-CTLA-4 can enhance the immune response to the tumour but can also induce autoimmune reactions
Activation of APC
APC express receptors for microbial molecules (PRR)
• Eg. carbohydrates, lipopolysaccharides (LPS)
Binding these pathogen-associated molecules activates APC – known as the danger signal
Leads to APC upregulation of MHC & co-stimulator molecules
Why is the activation of APCs important in T cell activation?
Ensures signal 2 to activate T cell-mediated response only occurs during infection
If a T cell receives signal 1 without signal 2, then it is functionally inactivated (anergic) & will not subsequently respond
Ensures only pathogen-activated APC can activate T cells
Co-stimulation: signal 3 (cytokines)
Dictate the differentiation of activated CD4 cells into different sub-sets of effector cells
Tells T cells what kind of T cell it needs to become depending on the cytokines that T cell makes
What are APCs?
Controllers of the immune response
Express MHC class II molecules
Dendritic cells – only function is to present Ag & crucial for activation of naïve T cells
– Dedicated to activate CD4 cells – don’t do anything else
Macrophages & B cells are also key APCs – present antigen in order to receive help from effector T cells
What are the 2 types of dendritic cells?
Myeloid – conventional DC (DC2,3)
• Potent APC
• Involved in activation of naïve T cells
Plasmacytoid DC (pDC, DC6)
• Important in viral infection
• Secrete several type I alpha & beta interferons
• Express TLR7&9 – sense viral antigens
Myeloid DC
- Key APC that initiate T cell responses
- Bone marrow derived
- Immature form found in epithelia (eg. skin)
- Do not express co-stimulatory molecules (B7) until activated/matured
- Induced to mature & migrate to lymph node following ‘danger signal’ activation/maturation
(Looking for bad things to happen – as soon as they detect something they become activated & take a piece of the damage to the lymph nodes to the B & T cells)
Activated myeloid DC
DC MHC I & II will be loaded with peptides from pathogens they encounters in peripheral tissues
Their levels of co-stimulatory molecules (eg. B7.1/2) will be very high
They will express high levels of adhesion molecules
Cross-presentation of DC cells
Some specialised DC (DC1) process exogenous Ag & present it via MHC class I molecules – Normally class II – Done by cross-presentation
This allows DC to activate CD8 T cells which can then kill other infected but non-APC which are expressing viral antigens on class I
Means both CD4 & CD8 can both be activated in the lymph node in response to DCs
Macrophages as APC
Function as scavengers/killers of pathogens but also important APC for extracellular pathogens (eg. bacteria & fungi)
Highly phagocytic – express many receptors for pathogen uptake (eg. carbohydrate & complement receptors)
Once activated by T cells secrete many inflammatory cytokines
B cells as APC
- Very poor at phagocytosis
- Internalise soluble Ag for processing & presentation by BCR
- Ag binding to BCR up-regulates B7 – B cells are capable of providing signal 2 to activate T cells
- Similar to DC – found in lymph nodes presenting to T cells
- Can recognise antigens in lots of different ways
- B cells act as Ag-specific APC
IL-2
A key cytokine for T cell survival
• Once T cell becomes activated they express a high affinity IL-2R
• IL-2 binding to IL-2R on activated T cells leads to T cell proliferation
Target of immunosuppressive drugs – eg. cyclosporin
When do T cells differentiate into effector T cells?
Following activation by APC
Type of effector sub-set generated is dictated by signal 3 (cytokines) from APC & the pathogen
Effector T cells
Display effector function when TCR engaged
– No longer require co-stimulation
– Change expression of adhesion molecules
No longer enter lymph nodes
But enter tissues via activated endothelia – at sites of infection & inflammation
Go where they are needed
Activation of CD8+ T cells
Require high levels of co-stimulator activity
Some CD8+ responses can be activated directly by APC
Or may require additional help from CD4+ T cells
