Linking: Signals 1 and 2 Flashcards
Describe activation of t helper and cytotoxic T cells
Signal 1 = pmhc:Tcr (the cd binds constant region of mhc)
Signal 2= b7 on apc: cd28 on t cell
Signal 3= cytokines
Name the 2 types of receptors
Extrinsic
Intrinsic
Describe intrinsic receptors
Receptor itself has Intrinsic kinase activity
Signalling initiated by dimerization and transphosphorylation
Kinase domain = part of receptor
Describe extrinsic receptors
Extrinsic kinase activity
Signalling initiated by RECRUITMENT of kinase and dimerization followed by transphosphorylation
Proteins recruited to receptor
What are molecular interactions determined by
Protein binding domains in their structure that have selective binding properties
Describe sh2 - molecule interactions
Sh2 domain = found in many proteins
Can recognize phosphorylated tyrosine on other proteins
Describe phosphorylated tyrosines - molecule interactions
phosphorylated tyrosines = phosphotyrosines
=binding sites for a number of protein-interaction domains
Describe result of molecule interaction
Leads to formation of multi molecular complexes around adaptor protein= once complete = then can have downstream effect
Describe phosphorylation/ubiquitination
Key mods involved in signalling
Ub = usually for degradation but can activate
phosphorylation= activates proteins
What are kinases
Proteins that phosphorylate other proteins —> lead to downstream cascade
What are phosphatases
Proteins that dephosphorylate other proteins
What happens to Ub proteins
Targeted for degradation usually by proteasome or lysosome
What can ub/phosphorylation do
Activate or inhibit signalling
Signalling must be turned off and on = regulation at every step
What is required for optimal T cell activation and proliferation
Costimulatory signals
Describe signal 1
Pmhc:Tcr engagement with coreceptor binding
Describe signal 2
Contact with costimulatory ligands
Also continues activation
Describe signal 3
Cytokines directing T cell differentiation into distinct effector cell types
Describe all signals
Result in intracellualr signalling = lead to change
Need all 3 signals to activation, proliferation and differentiation of T cells
How does Tcr initiate signalling
Involves Tcr complex =
Tcr, itam domains, cd3 and zeta chains
What happens when pmhc binds
When this occurs and coreceptor binds mhc (initiates first signal)
Binds constant region mhc = then lck
What is lck - initiate signalling
A co receptor associated kinase recruited and will phosphorylate Itams = lead to more signalling
Lck = lymphocyte specific protein tyrosine kinase
Lck = already activated, needs to be activated before can do job
What is zap-70 -initiate signalling
Recruited to itams and phosphorylated by lck
Zap70 binds to sh2 domain
What does zap70 kinase do
Activates many downstream signalling molecules
Describe whole process of Tcr signalling = series of events
Co receptor and Tcr binding —> lck recruited —> Itam phosphorylated — zap70 recruited —> Zap70 binds phosphorylated itams —> Zap70 phosphorylated —>downstream signalling effects
is co receptor and lck intrinsic or extrinsic
Lck not apart of receptor = has to be recruited
= therefore = EXTRINSIC
Summarize signal 1
Bind peptide mhc
Signal 1 results in intracellualr signalling =
Lck recruited = phosphorylates itams
Zap70 recruited and binds to phosphorylated itams
Zap70 phosphorylated and leads to many signalling cascades downstream
Signal 1 conclusions
Many pathways activated in parallel
Leading to transcription of many gene s= for activation, survival and differentiation of T cells
Why costimulation important t
Required for T cell activation, survival and proliferation
Name costimulatory ligands on apc
Cd80 = b7.1
Cd86 = b7.2
Name costimulatory ligands on Receptor on t clell
Cd28
Name types of costimulatory receptors
Positive costimulatory receptors
Negative costimulatory receptors
Describe positive costimulatory receptors
Facilitate activation
= cd28- receptor on T cells
Describe negative costimulatory receptors
Help Turn activation off
Ctla-4, pd1
Negative regulation
What does anergy mean
Non responsive
Anergic T cell =non responsive
Describe cd28
Transmembrane glycoprotein expressed as a homodimer
Where is cd28 found
On naive T cells AT BASELINE
What does cd28 bind
B7.1 = CD80 & B7.2=CD86
Describe cd80 and cd86
Homodimers
Both expressed by activated professional apcs
What type of interaction is cd28
Extrinsic bc need to recruiter pi3k = kinase, sh2 domain too
Not part of receptor
Describe whole process of cd28= 4 steps
1= binding to b7 molecules (cd80/86)
2=triggers phosphorylation of cd28 receptor by a kinase
3=recruitment of another kinase
4=additional signalling
What is needed for mhc molecules to be effectively expressed on cell Surface
Need peptide bound to them first
What happens if no costimulation
T cells become anergic
Not just neg regulation - not the same
Describe when clonal anergy
If no costimulatory signal
Important in regulation and decrease the probability of auto reactive T cells (decrease/regulate this)
T or F = anergic t cells can return to normal state and later response to costimulation
FALSEEEEEEEE
Anergic T cell can no longer respond to stimulation = it’s forever, will never go back
