Lecture 9- Activation and Differentiation of CD4+ T cells Flashcards
What are the basic components needed for Cd4+ t cell activation?
Cd4+ T cell
Antigen (must be presented)
Antigen-presenting cell= dendritic cell with MHC class II
These need to be touching each other, not far away.
How do cd4+ t cells enter lymph nodes?
Via HEVs. Naive T cells express chemokine receptor CCR7 which is attracted to CCL21 which is expressed on HEVs.
Where do the dendritic cells and t cells contact each other?
IN the paracortical area.
Then T cell leaves in lymph which goes via thoracic duct which drains into circulation. So its been activated it will move to site of infection.
Where does the dendritic cell go when its picked up an antigen?
Stay in the lymph node for a couple of days presenting its antigen, then will die.
How else can dendritic cells take up antigens?
There are resident DCs that hang around in the lymph node paracortex all the time. These capture and present antigens draining into lymph nodes from the tissue via lymphatics
Why is it good that recognising antigen is not enough for T cell activation?
Some DCs carry self antigens or harmless antigens so we dont want to respond to them all. Would get autoimmune systems and allergies.
What do you need to get full T cell activation?
- Antigen recognition with T cell
2. ALSO need 2nd signa-? interaction between co-stimulatory molecules!
What is the classic example of co-stimulatory molecules on T cell and dendritic cell?
CD28 on the T cell and CD80 or CD86 on the DC
Interact to provide this signal 2.
How is the signal 2 regulated? How is it switched on when there’s pathogens?
The co-stimulatory molecules can be upregulated by pathogens. DCs recognise pathogen-associated molecules via Pattern Recognition Receptors (PRRs) lots more co-stimulatory molecules. Also upregulates MHCII
What happens if the DC presents a self or harmless antigen?
You won’t get a signal 2 because there aren’t many co-stimulatory proteins being expressed on the DC because it hasnt recognised a pathofen so doesn’t activate the T cell
Just signal 1= T cell becomes anergic= unresponsive to antigen
What happens if T cell only receives signal 1?
Just signal 1= T cell becomes anergic= unresponsive to antigen
What is an important INHIBITORY co-stimulatory molecule?
CTLA-4. It inhibits CD28-CD80/86 signal -> this limits T cell activation
(stops cd28 binding)
What are the good and bad functions of CTLA-4??
-limits T-cell activation against self-antigens. V important for T cell homeostasis
HOWEVER ctla4 has been shown to limit t cell responses during a chronic infection or tumour cell. That’s bad. So has become a new target of therapy
What are signals 1 and 2?
Signal 1= T-cell recognise antigen presented by MHCII via its T cell receptor
Signal 2= a co-stimulaotry signal in addition to antigen recognition by T cell, e.g. CD28:CD80/86 interaction
(DCs are specialised to provide signal 2)
WHat cell adhesion needs to happen?
T-cells and DCs need to adhere to each other strongly to sllow t-cell activation to occur
What’s a classic example of adhesion moleculs for t cell:DC interaction?
DCs express adhesion molecule called ICAM-1. T cells express LFA-1 (also called integrin alphaLBeta2)
Describe LFA-1:ICAM1 interaction?
LFA-1 can bind to Icam1. When t cells enter lymph nodes and is scanning about, the affinnity of this LFA1:ICAM1 interaction is weak and loose, to allow it to scan along. Get loose adhesion between dendritic cell. Allows T cell to get close enough to sample the antigens. If the TCR finds its specific antigen presented by DC. Then CD4 on the T cell can interact with the MHC class II molecule on the DC. Solidifies the interaction. Get activation by signal 1. This changes the binding strength of this LFA1:ICAM1 so higher binding strength,
If the Tcell recognises antigen on DC what happens?
TCR and MHCII interact and then more signal 1 and then more MHC interactions so gets more strongly linked, stays around longer and then get signal 2 etc.
What happens if the T cell does not recognise antigen on the DC?
Dont get signal 1. Loose LFA-1:ICAM1 interaction isn’t strengthened so the T cell carries on and moves away until it finds its DC cell with the right antigen. If this doesn’t happen, the T cell leaves the lymph node and reenters lymphatics still in search of its special antigen
What is the immunological synapse?
The point of contact where the CD4+ T cells and dendritic cells interact.
What are the supramolecular activation clusters (SMACs)?
The clusters of molecules at T cell-DC interface
what clusters in the inner csmac and outer psmac?
cSMAC- TCR, CD$,CD28, MHC:peptide
pSMAC- LFA-1:ICAM-1
How does antigen binding and costimulation cause T cell activation?
Get intracellular signals triggered downstream of signal 1 and signal 2. So signal 1 and 2 trigger signalling pathways within the t cell which rpomote activation of that t cell
Does the TCR signal? What causes the activation of the T cell after the signals 1 and 2?
TC receptor itself cannot signal directly. It just bind to antigen.
Required interaction with the CD3 complex. This causes signals to be triggered inside the cell.
CD28 also triggers signals eg protein kinase cascades- alters gene transcription
What happens when a cd4+ t cell is activated?
T cells are first stimulated to proliferate- to increase the numbers of antigen-specific T cells= clonal expansion
What happens to allow clonal expansion?
Activated cd4+ t lls begin to express the receptor for the cytokine Interleukin 2 on their membranes. Allows early proliferation of cd4+ t cells.
Activated T cells also secrete IL2
The IL2 can act in an autocrine manner and a paracrine manner to drive T cell proliferation
ONce youve clonally expanded the cd4+ t cell what does it do?
The cd4+ t cells start to differentiate into effector cells. This all happens in the lymph nodes or spleen
