signal transduction for T cell activation Flashcard

do the alpha and beta chains of the TCR have cytoplasmic domains? how are signals from antigen sent intracellularly?
no, however the zeta and CD3 molecules have cytosolic domains
what are ITAMs? what do they do?
immunoreceptor tyrosine based activation motifs – common elements in the cytosolic domain of the signaling proteins, (zeta and CD3). these are sites for regulatory tyrosine phosphorylation, (both positive+negative)
what are lck, (p56lck – src family), and fyn, (p59fyn – src family), and ZAP70, (zeta associated protein)? what do they do?
protein tyrosine kinases that phosphorylate tyrosine residues, (ransfers a terminal phosphate group from ATP to the hydroxyl group of a tyrosine). they alter protein-protein binding and alter enzymatic activity.
what does p56lck do in a resting, (no antigen bound) T cell? is its ITAM phosphorylated?
nothing, it is phosphorylated, and thus inactivated. the zeta chain/C3 ITAMs however are NOT phosphorylated
what happens to p56lck when antigen binds to the TCR?
CD4 binds to the invariant region of Class II MHC and simultaneously, CD45 dephosphorylates and activates p56lck
what is p56lck? what does it do when CD45 activates it?
p56lck is a tyrosine kinase, and when CD45 activates p56, it phosphorylates ITAMs on CD3 and zeta chains
what does p59fyn do relative to p56lck?
p59fyn is a cytoplasmic tyrosine kinase, part of the src family and is is partially redundant to p56lck’s activity. the main difference is that p59fyn is found in association with TCR, even in resting cells
how is ZAP-70 activated? do they bind anywhere?
ZAP-70 is phosphorylated and activated, (presumably by p56lck/p59fyn). they also bind to the phosphorylated ITAMs on CD3/zeta chain
what does ZAP-70 do?
ZAP-70, once phosphorylated, is a tyrosine kinase that phosphorylates the gamma-1 subunit of phospholipase C and activates Ras, (G protein)
what does phospholipase C do when ZAP-70 activates it?
phospholipase C cleaves PIP2 into DAG and IP3, (diacylglycerol and inositol trisphosphate).
what does IP3 do when it is cleaved from PIP2 by phosphorylated phospholipase C, (along with DAG)?
IP3 opens a calcium channel to allow its release from the ER in the first wave of Ca++ release. IP3 then opens a pore in the cell membrane, creating the second wave of Ca++, this time extracellular
what do the Ca++ influx, (mediated by IP3) and DAG do
Ca++ and DAG activate protein kinase C, (PKC)
what does protein kinase C do once activated by Ca++ and DAG?
PKC phosphorylates negative regulatory peptide, IkappaB, thus activating NFkappaB
what does NFkappaB do once activated by protein kinase A?
NFkappaB is a transcriptional factor ultimately activating changing the gene expression and producing CD40L (CD40 ligand), IL-2 (interleukin 2), IL-2R (p55 alpha chain of the IL-2 receptor and upregulation of the beta chain)
other than activating protein kinase C, what other role does Ca++ play when lead to influx via IP3?
Ca++ complexes with calmodulin
what does calmodulin do when complexed with Ca++?
calcineurin, (serine/threonine phosphatase), is activated which dephosphorylates NFAT, thus activating it
what does NFAT do when activated?
NFAT is a transcriptional factor ultimately activating changing the gene expression and producing CD40L (CD40 ligand), IL-2 (interleukin 2), IL-2R (p55 alpha chain of the IL-2 receptor and upregulation of the beta chain)
are there immunosuppressive drugs that target NFAT activation? how do they work?
cyclosporine A complexes with cyclophilin and FK506, (tacrolimus) complexes with FKBP. both of these complexes INHIBIT calcineurin. this blocks NFAT, which blocks IL2 production, which shuts immune responses down because you don’t get T cell expansion
other than NFkappaB and NFAT, what is the third transcription factor activated in T cell signaling? what is the first step in it’s activation?
AP1, Ras has to be activated by ZAP-70
what is Ras?
Ras is a GTP binding protein, (inactive when GDP is bound, activated by replacment with GTP by a GEF- guanine exchange factor)
how does ZAP-70 activate Ras?
ZAP-70 is a protein tyrosine kinase that hooks up with adaptor proteins, (SH2, SH3 domains), that hook up with a GEF that replaces the GDP on inactive Ras with GTP, thus activating it
what does Ras do once activated?
Ras binds to a MAP, (mitogen activated protein), kinase called Raf
what does Raf do?
Raf, once activated by Ras, sets a MAP kinase cascade in motion that phosphoylates Elk 1
what does Elk 1 do once activated by Raf?
Elk is a transcriptional factor that regulates the transcription of cfos
what does cfos transcription by Elk1 do?
fos the only factor we will talk about today that has to be synthesized de novo, and once it is, it forms a complex with cytosolic jun, creating the AP1 transcriptional complex
where does jun come from?
cjun is a cytosolic transcription factor that is activated by phosphorylation by JNK kinase, (jun-n-terminal kinase) which is activated by a MAP kinase cascade regulated by Rac, (another G protein closely related to ras)
what do jun and fos do once fully activated?
form AP-1 a transcription factor
what does AP-1 do?
AP-1 is a transcriptional factor ultimately activating changing the gene expression and producing CD40L (CD40 ligand), IL-2 (interleukin 2), IL-2R (p55 alpha chain of the IL-2 receptor and upregulation of the beta chain)
of the four T cell activation pathways, NFkappaB, NFAT, cfos, and jun, which can be targeted for immunosuppressive therapy?
NFAT, by cyclosporine and tacrolimus which shut down calcineurin
what is mutated Ras associated with?
neoplastic transformation, due to mutated GTPase activity

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