T cell signalling Flashcards
T cell activation gieves signals for survival, expansion, and functional differentiation. What metabolic changes help enable rapid proliferation?
Metabolic changes- switch from ox phos to glycolysis, and increased glutaminolysis to provide materials for DNA replication and protein production.
What proteins make up the CD3 receptor complex.
CD episilon, CD3delta, CD3 episilon epsiolon. Then two CD3 zeta chains containing ITAMs.
What kinases help to phosphorylate the tyrosine of the CD3 zeta ITAMs?
Lck (linked to CD4) and fyn.
After binding to phosphorylated tyrosines on ITAMs, what molecule does ZAP70 activate? And how is that protein localised and why?
ZAP70 phosphorylates and activates the scaffold protein LAT. LAT has lipid anchors that localise it to the lipid rafts of the membrane, where biologically activated phospholipids are (PIP3 and PIP2 important).
What are 2 important proteins that are linked to the LAT protein scaffold?
PLC-y and SLP76. Others are GADs and Grb2.
What two signalling molecules does the kinase ITK help activate?
helps phosphorlyate and activate PLC-y and SLP76.
What are the targets and products of PLC-y mediated reactions?
Breaks down PIP2 into DAG (drives PKC activation) and IP3.
How does IP3 generation lead to NF-AT activation of target genes?
IP3 stimulates ER calcium release. Ca2+ binds caldmoulin which activates calreticulin. Calreticulin phosphatase removes phophsate of NF-AT. Dephosphorylated NF-AT transcolates to the nucleus to mediate changes in gene expression.
What two things can you add to activate T cells artificially?
PMA (DAG substitute) and ionomycin.
Grb2 and SOS are attracted to LAT and GRB2 via their SH2 domains. They activate a Ras GRP (guanine nucleotide releasing protein). What happens next?
GDP associated with Ras is removed. GTP binds to GTP to make an activated form of Ras which activates MAPKKK (Raf), MAPKK (MKK1), MAPK (ERK1) cascade.
classic activatory co-stimulatory interactions? What signalling cascade does it use?
T cell CD28: CD80 (B7)/ CD86 interaction. Signalling via PI3K.
Inhibitory co-stimulatory molecule interactions
T cell CTLA-4: CD80 (B7). Inhibits PKB/ AKT through phosphatase action of PP2A.
PD-1: PDL SHP2 inhibits PI3K.
What does the CD28: CD80 signalling cascade look like?
PI3K will phopshorylate PIP2 to PIP3 (no longer targeted by PLC-y). PIP3 recruited molecules like ITK, PDK1 and PKB via their PH domains. This leads to PKB activation.
What cytokine receptors include the common gamma chain in IL2R y chain family? There are 6.
Il-2, Il-4, Il-7, Il9, IL-15 Il-21.
what cytokine receptor chain and JAK are associated with SCID?
IL-2R common y chain and JAK 3.
