11 T Cell receptor activation II Flashcards
how is signaling important for medicine?
The vast majority of pharmaceuticals target the signaling proteins. (The majority of new drugs are targeted to signaling proteins)
which part of the T cell receptor interacts with the MHC complex?
The variable regions (alpha and Beta) of the TCR
what is the complimentary determining region (CDR) of TCR?
The part that interacts with the antigen and MHC
CDR1 and CDR2 are encoded by which region of the TCR? what about CDR3?
CDR1 and CDR2 are encoded by the V regions
CDR3 is encoded by the junction of V, D, and J.
The alpha and beta chains of the TCR make up 3 complementary regions that control the activation/interaction of the TCR. What are these 3 motifs (regions) called?
CDR1 (binds both MHC and antigen)
CDR2 (binds mainly MHC)
CDR3 ((binds mainly antigen)
T/F Each TCR has variable contacts with the antigen/MHC complex?
True. These variations in binding are important for allowing flexibility in the binding of the pool of TCR’s to multiple peptides.
what do the MHC classes with bound antigen bind to on the T cell?
1) TCR and CD8 or CD4
The binding occurs simultaneously
what is considered to be a co-receptor? what is the function of a co-receptor?
1) Co-receptors are CD4 and CD8’s
2) The function of a co-receptor is to enhance the sensitivity of the T cell to and antigen/MHC complex
T/F CD8 is a monomer?
False. CD8 is a hetero-dimer, and CD4 is a monomer.
do CD4 and CD8 interact at the peptide binding cleft of MHC complexes?
No, they interact with invariant regions which are distant to the cleft.
If you do not have CD4 or CD8 cells, will the T cells become activated with the TCR and MHC complexes?
Yes, but they are greatly reduced! you need the co-receptors to be present for an efficient activation. They increase the responsiveness by 10-100x.
what makes up the T cell receptor complex?
The normal T cell receptor with alpha and beta units, and two lateral CD3 units which act to transmit intracellular signals.
what makes up the parts of the CD3 complex?
CD3 gamma, delta, epsilon, and zeta
Possibilities are:
CD3 epsilon/delta (heterodimer)
CD3 epsilon/gamma (heterodimer)
CD3 zeta/zeta (homodimer)
What is an ITAM?
Immuno tyrosine activation motif.
Each CD3 combination has at lease one ITAM motif used for signaling.
What causes the ITAM (of TCR subunit) to send a signal?
phosphorylation.
Binding the TCR to the antigen/MHC complex recruits the CD4 or CD8. These co-receptors activate tyrosine kinase (Lck) which phosphorylates the ITAMS. Phosphorylated ITAMS recruit ZAP 70. ZAP 70 activates LAT.
what does ZAP 70 do?
Phosphorylates and activates LAT which results in most of the down stream signaling within the T cell.
What does phospholipase gamma do? what does it make?
1) cleaves 4,5 phosphytidyl inositol phosphate.
2) It makes:
DAG
Inositol 1,4,5 phosphate [IP3]
what happens after ZAP 70 phosphorylates LAT?
SLP 76 binds LAT and recruits the tyrosine kinase ITK. At the same time, PLC gamma1 binds LAT and becomes phosphorylated by ITK. This sends the signal.
How is PIP3 formed?
PI is phosphorylated at the 3rd position on the head group by PI3K. This forms PIP3. This is reversible.
Besides favoring the formation of PIP3, what else does PI3K do? (phospho inositol 3 kinase)
It activates Akt (a serine/threonine kinase)
What does Akt do?
regulates: cell survival apoptosis protein translation Transcription Factor activation Metabolism
kinase cascades are essential for activation of transcription factors. The Ras pathway is well understood, how does it work?
1) activation of LAT, activates Ras
2) Ras induces Raf
3) Raf activates MEK and Erk
4) Activated Erk drives gene transcription.
What does the influx of Ca+ do inside the T cell?
How does it work?
1) activates the transcription factor NFAT.
2) Influx of calcium binds up calmodulin, and the calcium bound calmodulin binds calcineurin. This complex (calmodulin/calcineurin) dephosphorylates NFAT allowing it to drive gene transcription.
why would you want to target calcineurin with a drug?
You could do so if you wanted to design an immunosuppressant.
what happens when you activate IKK?
The IKK degrades Ikb or P100 which are inhibiting NF-kb and RelB respectively. Degrading P100 forms P52 which together with RelB can activate transcription. NF-kb also drives gene transcription.
T/F transcription factors control the transcription of multiple genes?
True. Each gene promoter is regulated by the function of multiple transcription factors.
T/F Activation of TCR causes actin polymerization and changes in cell morphology? How long would this take?
True, it normally occurs within minutes.
why are changes in t cell morphology (actin) needed?
1) For maximal adhesion and TCR/MHC contact.
2) Formation of lamellipodia and phyllopodia.
recruitment of proteins to what, drives actin cytoskeletal rearrangements?
LAT
What activates Arp2/3 to induce actin branching?
Wasp
Rac
CDC42
mutations in Wasp and Rac2 cause what?
T cell defects
what recruits Wasp to LAT?
Nck
What is the full order of activation with a TCR and a CD4?
LCK ( on CD4) ITAMS (on TCR) ZAP 70 LAT + (SLP 70 & ITK) PLC gamma (phosphorylated) PIP --->DAG and IP3 (Ca+ release)
What makes PIP? What makes IP3?
PIP made from IP3 and PI3K ( activates atk)
IP3 made from PIP and PTEN
Cascade order?
Ras Raf mek Erk Transcription factors
