Lecture 8: Immune Receptors and Signal Transduction I Flashcards
Activation of NF-kB pathway
Activated IKK phosphorylates IkB and induces poly-ubuiquination of IkB
IkB is then degraded and cytoplasmic NF-kB dimers are released and translocated to nucleus
Adaptor protein domains
May contain several SH2 and SH3 domains
May have tyrosine residues for docking sites for proteins with SH2 domain
May have proline-rich sequence for binding proteins with SH3 domain
Number of ITAMs phosphorylated represents
The # of phosphorylations is a cytosolic interpretation of Ag affinity to TCR
The stronger/prolonged binding of Ags to TCR results in increasing # of phosphorylated ITAMs
Covalent addition of lipids may promote
Plasma membrane localization of signaling molecules
FcyRIIB
Inhibitory receptor found on B cells and myeloid cells
Strong TCR signals are required for
Negative selection of T cells and their death by apoptosis
TCR complex consists of
alpha/beta TCR non-covalently linked to CD3 and Zeta proteins
Both a/b chains have carboxyl terminal cytoplasmic tails 5-12 AAs long
CD3 and zeta proteins serve as signal-transducing subunits
VAV
Guanine nucleotide exchange factor
No expression of LAT in a cell causes
Defective in TCR mediated signaling
No mature a/b T cells would be found
SH3 domain
50 amino acids that bind to proline-rich stretches
Formation of pMHC/TCR/CD4 complex provides
First signal through TCR associated CD3 complex to T cell
- this signal is necessary but not sufficient to stimulate naïve T cell to proliferate and differentiate
- also requires group of costimulatory molecules
Tyr416 site on Src
Can be auto-phosphorylated, opening pocket and allowing substrate to gain access
Result when TCR engagement occurs in the absence of CD80/28 co-stimulation
Calcium mediated signals induce the activation of NFAT only
NFAT elicits expression of Anergy inducing genes which inhibit T cell function and induce status of T cell unresponsiveness
CD8 structure
Two related chains called CD8a and CD8b
- both have a single extracellular Ig domain
- both have highly basic cytoplasmic tail about 25 AAs long
Tyr527 site on Src
Phosphorylation of Tyr527 inactivates Src through interaction of Tyr527 with SH2 domain, which folds Src into a close, inaccessible bundle
-dephosphorylation at this site activates it
Ras-MAP kinases, activation of AP-1 events
Ag recognition- CD4/CD8 associated Lck is activated
Lck phosphorylates ITAMs of z-chain
ZAP-70 binds z-chains and self-phosphorylate to activate
ZAP-70 activates adaptor protein LAT
LAT binds GADS adaptor (Grb2) that docks GTP/GDP exchange factor SOS
SOS converts Ras-GDP to Ras GTP which activates MAP kinase and ERK
The cascade activates AP-1
Anergy can be induced by
Substimulatory levels of Ags in the absence of:
- CD28:CD80 interactions between costimulatory receptors on T cells and counter receptors on APCs
- A costimulatory signal provided by soluble cytokines
LFA-1:ICAM-1 complex and pMHC:TCR:CD4 complex and CD2:LFA3 and CD28L:CD80/86 complex
LFA/ICAM complex move away from MHC/TCR/CD4 complex while CD2/LFA3 and CD28/CD80/86 complexes move toward the MHC/TCR/CD4 complex
Clonal anergy
Describes T cell unresponsiveness at cellular level
Hyporesponsive state characterized by reduced capacity to synthesize IL-2
Anergic T cells do not proliferate in response to Ag
SH2 domain
100 amino acids that bind to phophotyrosine-containing peptides
-Present in Syk and ZAP-70 tyrosine kinases
Which terminus of histones is modified
The N terminus
Weak TCR signals are required for
Positive selection of T cells in the thymus
LAT
Integral membrane protein that functions as adaptor
CD4 structure
4 extracellular Ig-like domains
Highly basic cytoplasmic tail 38 AAs long
SH4 domain
Contains myristic acid moiety, essential for its localization to the inner surface of cell membrane
PH domain
Found in Tec family kinases and recognize specific phospholipids
-Btk tyrosine kinase
Cytoplasmic tails of CD3 domain contain ____
Compare to cytoplasmic tails of TCR
Cytoplasmic domain of CD3 contain ITAMs, while those of the TCR do not
GADS
Cytosolic adaptor protein
Adaptor protein catalytic activity
They have no catalytic activity
Immunologic synapse is imitated by
TCR recognition of pMHC
SLP-76
Adaptor protein with proline rich domain and SH2 binding domains
SH1 domain
Catalytic domain
TCR complex contains __ signaling chains and __ ITAMs
6 signaling chains
10 ITAMS
