15 – Linking Innate & adaptive: Signals 1 & 2 Flashcards
Antigen presentation 3 signals:
Signal 1 =pMHC:TCR engagement
With co-receptor binding
Signal 2 = contact with costimulatory ligands
Costimulatory signals = required for optimal T-cell activation & proliferation
Signal 3 = cytokines directing T0-cell differentiation into distinct effector cell types
ALL 3 signals = result in intracellular signaling –> leading to CHANGE
Receptors – for
signaling
Phosphorylation for intracellular signals
2 types of receptors & what are they
With intrinsic kinase activity
-Intrinsic receptors
-Signaling initiated by dimerization & transphosphorylation
-Receptor itself has intrinsic kinase activity
With extrinsic kinase activity
-Extrinsic receptors
-Signaling initiated by recruitment of kinase & dimerization –> transphosphorylation
Molecular interaction = determined by
domains in their structure that have selective binding properties
SH2 domain
Found in many proteins
Can recognize & bind phosphorylated tyrosine on other proteins
Phosphorylates tyrosine (phosphotyrosine) = binding sites for several protein-interaction domains
Only when complete – can have downstream effect
Formation of multimolecular complexes around
adaptor proteins
Phosphorylation & ubiquitination
Key modifications involved in signaling
Kinases
Proteins that phosphorylate other proteins
Once activated – lead to downstream cascade
Phosphates
Proteins that dephosphorylate other proteins
Ubiquinated proteins
Targeted for degradation by proteosome OR in lysosome
modifications – can function to
ACTIVATE or INHIBIT signaling
Signaling must be turned off or on
Always regulation happening
TCR complex
TCR
ITAM domains
Immunoreceptor tyrosine-based
activation motifs
CD3
Zeta chains
…initiate 1st signal
co-receptor very important
When pMHC:TCR binding happens in … & … binds to …
in constant region & coreceptor binds MHC
Lck – co-receptor associated kinase recruited & phosphorylate ITAMS – lead to more signaling
ZAP-70 – recruited to ITAMs through SH2 domain & phosphorylates by Lck
Lck =
Lymphocytes-specific protein tyrosine kinase
TCR signaling complex (7 steps)
1.Co-receptor & TCR binding
2.Lck recruited
3.ITAM phosphorylated
4.Zap-70 recruited
5.Zap-70 binds to phosphorylated ITAMs
6.Zap-70 phosphorylated
7.Downstream signaling
Signaling leads to transcription
Signal 1
intracellular signaling
- Lck recruited & phosphorylates ITAMs
- Zap 70 recruited & binds to phosphorylates ITAMs
- Zap 70 phosphorylated & leads to many signaling cascade downstream
4.Many pathways activated in parallel
5.Leading to transcription of many genes
Signal 2 – Costimulation
T cell activation/survival/proliferation
Costimulatory ligands & receptors
Ligands on APC
CD80 – B7.1
CD86 – B7.2
Receptor on T cell
CD28
Positive costimulatory response facilitate
example:
activation
-CD28
Negative costimulatory receptors help:
turn activation off
CTLA-4
PD-1
-Produces Anergic T cell
-Anergy = non-responsive
CD28
Transmembrane glycoprotein – expressed as homodimer
Found on all naïve T cell at baseline
Binds B7.1 (CD80) & B7.2(CD86) & homodimers
Both expressed by activated APCs
-Mature /professional DCs activate APC
CD28 signaling (4 steps)
- Binding to B7 molecules – CD80/86
- Triggers phosphorylation of CD28 receptor by a kinase
- Recruitment of another kinase
- Additional signaling – downstream
Clonal anergy
if a costimulatory signal is absent – important in regulation & decrease probability of autoreactive T cells
Anergic T cell stay
anergic
Absence of costimulation = T cell becomes
anergic = nonresponsive
