Costimulatory signals Flashcards
What is co-stimulation?
A secondary signal which immune cells reply on to activate an immune response in the presence of APCs
For lymphocytes activation (T and B cells) Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors. They promote T cell proliferation and survival.
Once naive T cells have been developed in the thymus they gave to home to the lymph nodes before they meet the APC for antigen signalling activation. What the causes the homing?
- This is done via specialised blood vessels – high endothelial venules (HEVs) and stromal cells which secrete the chemokine CCL21
- The higher the concentration of chemokine, the more the cell will home towards the source
- The CCR7 receptor on the naïve T cell recognises the CCL21
- DCs also have a receptor for CCL21 so is also attracted to the lymph nodes
- The T cell CCR7 receptor also recognises DCs secreting CCL19 for attraction
- They also need L-selectin expression, a selectin molecule for “rolling” into the lymph node
What are the 3 signals needed for APC and lymphocyte activation for a good immune response?
- Antigen Presenting from MHC on APCs
- Costimulation for upregulation (sometimes deregulation) of the response
- Cytokine signals
Antigen Presentation with the MHC on the APC e.g. the dendritic cell needs to be recognised by the T cell receptor. Which signalling molecules are necessary for this activation?
a. The initial interaction with the DC uses LFA-1, a cell adhesion protein on the naïve t cell
b. LFA-1 on the naïve T cell binds to ICAM-1 on the DC
c. Binding sends a signal and causes conformational change, increases affinity and prolongs cell-cell contact including the TCR binding to the MHC and the CD4 molecule
These signals initiated by the T-cell and B-cell antigen receptors are essential for lymphocyte activation, and determine the specificity of the adaptive immune response that is initiated. However, signaling from the antigen receptor is not on its own sufficient to activate a naive T cell or B cell
The second signal needed for a good immune response is costimulation. For T cells what costimulatory molecules are used and how do they interact with the APC and the TCR?
For T cells, the costimulatiory molecule is CD28, located on the T cell. It interacts with B7.1 or .2 on the APC (DC) causing activation.
Activation of T cells without co-stimulation may lead to T cell anergy, T cell deletion or the development of immune tolerance.
- CD28 on the naïve T cell binds to either B7 molecule on the APC
- Tyrosine molecules on CD28 in the cytoplasmic domain then get phosphorylated by Lck
- This causes the recruitment of PI 3-kinase which can NOW bind to PIP2 on the inner membrane of the T cell. This then forms PIP3
- PIP3 can then bind and recruit PDK1 and Akt and phosphorylate and activate Akt, which promotes cell survival and increased cellular metabolism and also it can phosphorylate RNA-binding protein NF-90
a. NF-90 then can translocate from the nucelus to the cytoplasm and binds to and stabilizes the IL-2 mRNA, leading to increased IL-2 synthesis - PIP3 also recruit Itk which can phosphorylate PLC-gamma (-g)
- PLC-g then binds to a scaffold build by T cell signalling made of LAT and Slip76, bridged by adaptor molecule Gads (?)
- This fully activates the PLC-g
- Finally PIP3 recruits Vav, which leads to cytoskeletal reorganisation and activates Cdc-42
T cell costimulation can be regulated (either enhanced or decreased) in Naive T cells. Describe enhancement and decreasing T cell costimualtion and the molecules necessary for it.
Enhancing Co-stimulation:
- ICOS -> an inducible co-stimulator which binds ICOSL ((B7-H2), a structural relative of B7.1/.2 which is produced on activated DCs. monocytes or B cells).
ICOS regulates the expression of cytokines (IL-4 and IFN-y) which enable CD4 T cells to function as helper cells for B cell isotope switching. ICOS is expressed on T cells in germinal centers within lymphoid follicles, and mice lacking ICOS fail to develop germinal centers and have severely diminished antibody responses.
- CD40L
It is located on T cells where it binds to CD40 on DCs to increase co-stimulatory proteins. Mice lacking CD40 show poor T cell proliferation
Decreasing Co-stimulation:
- CTLA-4 (CD157)
It acts as a receptor for B7 molecules but binds with x20 avidity than CD28 (acts as a competitor). However, it inhibits the T cell by making them less sensitive to costimulation than naive T cells. This restricts IL-2 production
Signal 3 of T cell activation is the production of cytokines by the APC which trigger the T cell to become a specific effector cells. Which cytokines are produced for specific T cells?
Il-2 -> most naive t cells produce IL-2 after CD28 costimulation. They are induced at the same time as G1 phase of T cell development which also induced the high affinity IL-2 A receptor which can respond to lower levels of IL-2. IL-2 is essential for TR cell proliferation and survival, Treg cell maintainance and they effect the balance of effector and memory T cells.
Other Cytokines produced by APC: Pairs of cytokines can activate mature differentiation of effector cells without antigen recognition
The pair includes one cytokine that activates a receptor that signals via a STAT factor. It also include a cytokine that activates a receptor that signals via NFκB—typically a member of the IL-1 receptor family.
Give some cytokine examples and what T cells they cause to differentiate.
TH1 activation
- IL-12 (STAT4) and IL-18 induces production of IFN-γ. This stimulates T-bet, a transcription factor which helps the T cell produce IL-2 and IFN- γ and causes differentiation into TH1 cells
TH2 activation
- TSLP (STAT5) and IL-5 produce IL-5 and IL-13
TH17 activation
- Stimulated by IL-23 (STAT3) and IL-1 produce IL-17 and IL-22
In this way, mature effector CD4 T cells acquire innate-like functional properties that allow them to amplify different types of immune responses without the requirement for antigen recognition. Sometimes IL-1 cytokines are involved (fIL-18 and IL-1) and are produced by inflammasome activation in myeloid cells.
Although the precise role of non-cognate activation of effector T cells by cytokines is not clearly defined, it may provide a mechanism by which tissue-resident memory T cells could be rapidly recruited in recall, or memory, responses.
B cells also require costimulation for an effective immune response. But what is the first signal required for B cell activation?
B cells process and present antigens that bind to their surface immunoglobulin:
• Binding of antigen by surface Ig leads to receptor mediated endocytosis
• Antigen delivered to MHC class II for presentation
• Will therefore stimulate helper T cells that recognise the same antigen as the B cells
What are the signals needed for effective B cell activation?
For effective activation, the naive B cell needs:
- The BCR recognising the pathogens antigen in its native form, usually via PRRs such as TLRs
- T cell cytokines (IL-4,-5,-6)
- Costimulation through the costimulaotry molecule CD40L located on the TH2 cell interacting with CD40 on the B cell
How do follicular T helper cells (TFH) help B cell activation?
When TFH cells are activated (Naïve T cell activation), they start to upregulate CXCR5 which allows the TFH to move via chemotaxis towards the B cell zone in the lymph node. This helps B cells produce CXCL13 which homes the B cell towards the GC for production into B effector (plasma) high affinity antibody-producing cells and B memory cells. These work against the original antigen
