Antigen Receptor Signaling and T-cell Activation - Kane Flashcards
What is Lck and what is its function?
Lck is a Src tyrosine kinase closely associated with the co-receptors of T-cells and plays a role in the phosphorylation cascades involved in TCR signaling.
TCR signaling: Step 1
TCR binds to MHC-peptide and co-receptor brings Lck to close proximity of ITAMs
TCR signaling: Step 2
Lck phosphorylates ITAMs in zeta chains and CD3 chains of the TCR.
TCR signaling: Step 3
Zap70 is recruited to ITAM phosphorylated tyrosines and Zap70 gets phosphorylated by Lck.
TCR signaling: Step 4
Zap70 phosphorylates LAT and PLCy1, and PLCy1 associates with LAT
TCR signaling: Step 5
PLCy1 cleaves phosphoinositol substrates and creates second messengers such as DAG and IP3
TCR signaling: Step 6
Second messengers activate txn factors such as NF-AT
What is an SH2 domain and what does it do?
SH2 domains are specific regions of proteins that can mediate direct binding of phosphorylated tyrosine substrates. For example, SH2 domains Zap70 can bind to z-chains phosphorylated by Lck.
What is an SH3 domain?
SH3 domains are specific regions of proteins that recognize poly-proline residues.
Describe the PLCy1 pathway
Upon activation of PLCy1, it cleaves PIP to generate 2 second messengers, DAG and IP3.
What does IP3 do?
IP3 is a second messenger that associates with the ER and causes an efflux of intracellular Ca. Efflux of Ca, causes activation of calcineurin which dephosphorylates NF-AT (txn factor).
What do the drugs cyclophilin and FKBP do?
These drugs inhibit calcineurin preventing activation of NF-AT. This shuts down T-cell activation despite upstream signaling.
Describe co-stimulation of T-cells?
CD28 on T-cells interact with B7 receptors on APCs to stimulate activation. Absence of this signal can lead to a state of anergy.
How is co-stimulation regulated? Describe how this is druggable.
CTLA on T-cells regulate stimulation by B7 on APCs by competitively inhibiting CD28. Drugs such as CTLA-Ig can competitively inhibit B7 to prevent co-stimulation of T-cells.
How can you enhance T-cell responses via drugs involved in the co-stimulation pathway?
You can target CTLA to inhibit it so that it cannot dampen co-stimulation of T-cells via CD28 and B7 interactions.