Breakout 4

Question 1

requirements for effective TCR and BCR signaling

Answer 1

threshold of receptor engagement
affinity of antigen
movement into lipid rafts
engagement of TCR and BCR are required for peripheral activation
TCR and slg must complex with additional signaling molecules in order to transmirt signals when engaged

Question 2

threshold for receptor engagement

Answer 2

500-1000 for T cells
20 for B cells
costimulation lowers the threshold of antigen for both:
T cells: CD28 costim
B cells: CD40 costim

Question 3

affinity of antigen

Answer 3

Higher affinity, higher engagement
T cells must have TCRs engaged for at least 20 hours
B cells must have BCRs engaged for at least 3-4 hours

Question 4

movement into lipid rafts

Answer 4

Movement is critical to get BCR and TCR in proximit to signaling molecules required for activation

Question 5

Signal transduction through the T cell receptor and the B cell receptor
Important molecules:

Answer 5

Immunoreceptor tyrosine-based activation motifs (ITAM)
ZAP-70 (zeta-chain associated protein)
CD28 signaling increases PLC-gamma activation to increase IL-2 production to levels required for full T cell activation

Question 6

ITAM

Answer 6

Contain two tyrosine residues that become phosphorylated by specific tyrosine kinases after engagement
Once phosphorylated, can bind to Sh2 domain of signaling proteins
CD4 engagement of MHC II near TCR induces Lck to phosphorylate ITAM residues on CD3 and zeta chains
Phosphorylated ITAM motifs recruit ZAP-70 to initiate downstream signaling of TCR

Question 7

ZAP-70

Answer 7

Limited expression throughout the body
ZAP-70 is critical in phosphorylating downstream mediators of TCR signaling
ZAP-70 deficiency in humans leads to loss of peripheral CD4 and CD8 T cells and xhibit SCID phenotype

Question 8

Pharmacologic inhibition of TCR and BCR pathway in the treatment of disease

Answer 8

T cells are involved in:
Multiple sclerosis
Rheumatoid arthritis
Tumors
Graft rejection

Question 9

Great inhibitor of T cell activation

Answer 9

Completely shut down TCR signaling
T cells specifically
ZAP70
PKC-theta

Question 10

Current inhibitors that decrease TCR signaling

Answer 10

Cyclosporin A and FK506
Act to inhibit calcineurin activity and decrease in NF-AT activation
Effective atopic dermatitis, RA, MS, T1DM

Question 11

Similarities of TCR and BCR signaling pathways

Answer 11

activation of Src family kinases
Both Lck and Lyn phosphorylate ITAM motifs
Recruit Syk family domains
ZAP-70 and Syk activate linker molecules and tyr kinases
Activate PLC-gamma

Question 12

Differences of TCR and BCR signaling pathways

Answer 12

ZAP-70: T cell specific
Syk: NOT B cell specific
Activation of different isoforms of PKC:
- T cells: PKCθ
- B cells: PKC (not specific)

Question 13

BCR signaling

Answer 13

Slg associates with igalpha and igbeta to initiate signaling
ITAM motif associates with src family members: Fyn, Blk, Lyn
After slg crosslinking, Lyn phosphorylate ITAMs
Syk binds Igbeta chain and amplifies signal by phosphorylating other Syk proteins in proximity

Question 14

syk protein and BCR signal transduction

Answer 14

B cells do NOT express ZAP-70 and Syk acts in homologous fashion
Syk initiates the activation of key signal transducing molecuels for B cells activation
Syk constitutively activated in numerous B cell lymphomas

Question 15

Outcomes of BCR-induced signal transduction

Answer 15

Costimulatory molecules: NF-kB critical in increasing CD80/CD86 levels
Myc-critical for inducing B cell proliferation
Anti-apoptotic molecules: NF-kB critical in increasing levels of Bcl-2, Bcl-xL, and A1
BCL-6 and BLIMP influence plasma cell and memory B cell differentiation

Question 16

Great inhibitor of B cell activation

Answer 16

Completely shut down BCR signaling
B cells specifically
Targeting Syk has some promise

Question 17

Syk inhibitors

Answer 17

leukemia/lymphomas-syk inhibitor induces apoptosis of tumors the B cell lineage