10. Lymphocyte receptor signalling Flashcards
a primary response to an antigen causes:
clonal expansion of antigen-reactive T or B cells
what is the function of signal transduction pathways
control transcriptional and metabolic pathways
determine lymphocyte function
membrane receptors have 3 domains:
- extracellular domain: binds ligand
- transmembrane domain: span the PM
- cytoplasmic domain: participate in signal transduction
ligands for TCR and BCR
TRC: peptide + MHC
BCR: antigen
what is the immunological synapse
the space between the T cell and APC where receptor-ligand binding occurs in order for signal transduction to happen
T cells are activated through 2 signals…
signal 1: MHC + peptide on APC binds TCR
signal 2: B7 on APC binds CD28 on naive T cell (costimulatory signal)
what is the costimulatory signal in T cell activation
B7 binds CD28
B7 is only expressed if infection is present
what makes up the immunological synapse
TCR and MHC:peptide complex
co-stimulatory molecules
co-receptor and MHC:peptide complex
cell-adhesion molecules
what is CD3
the cytoplasmic domain of the TCR that relays the signal from the synapse so that signal transduction can start
what are ITAMs
immunoreceptor tyrosine-based activation motifs
cytoplasmic aa sequences containing tyrosine that are targets of phosphorylation
docking sites for other proteins
mediate interactions with cytoplasmic protein-tyrosine kinases
what are the protein-tyrosine kinases in TCR signal transduction
Lck and ZAP-70
what is the key event in TCR signal transduction
the phosphorylation of ZAP-70 by Lck
induces 3 signal transduction pathways
1st signal transduction pathway of TCRs: NFAT actiavtion
- phosphorylation and activation of PLCy
- cleavage of PIP into IP3 and DAG
- IP3 signals calcium stores to open
- Ca2+ diffuses through the cell
- calcineurin is activated and dephosphorylates NFAT
- NFAT acts as a TF and activates genes for T-cell expansion and differentiation
2nd signal transduction pathway of TCRs: NFkB activation
- phosphorylation and activation of PLCy
- cleavage of PIP into IP3 and DAG
- DAG activates PKC
- PKC activates the NFkB through destruction of associated IkB protein
- NFkB acts as a TF and activates genes for T-cell expansion and differentiation
3rd signal transduction pathway of TCRs: AP-1 activation
- phosphorylation and activation of PLCy
- cleavage of PIP into IP3 and DAG
- DAG associates with RAS
- RAS triggers MAP kinase cascade to activate Fos
- Fos interacts with Jun to produce AP-1
- AP-1 acts as a TF and activates genes for T-cell expansion and differentiation
what is the most important gene for T-cell activation
IL-2
what activates the Jun proteins in TCR signalling
a co-stimulatory signal provided by CD28
multiple signalling pathways for TCR signalling converge on the…
IL-2 promoter
- TCR and CD28 activate PLC-y which leads to activation of TFs on the IL-2 gene
what is the role of Ig-B and Ig-a in the B-cell receptor
signal transduction during B-cell activation (similar to CD3 of the TCR)
what is required for BCR signal transductions to be activated
clustering of BCR complexes on the B-cell surface
what proteins are part of the Src family kinases
Blk, Fyn, Lyn
what makes up the BCR co-receptor
CR2
CD19
CD81
B-cell coreceptor binding for signal transduction activation
- CR2 binds to iC3b and C3d (required for costimulatory signal
- CD19 has a cytoplasmic domain for signalling events
- CD81 stabilizes the coreceptors
signalling at the Ig receptor complex
Syk (similar to ZAP 70) is a kinase which induces 3 signal transduction pathways: NFkB, NFAT, AP-1
GEFs catalyze the exchange of guanine nucleotides on binding proteins Ras and Rac so that AP-1 can be produced
inhibitory receptors on lymphocytes down-regulate immune responses by…
interfering with co-stimulatory signalling pathways
inhibitory vas acitvating receptors of T cells
naive = activating = CD28: one dimer engages with one B7 (stronger adhesion)
activated = inhibitoy = CTLA4: 2 dimers bind to 2 B7s (higher affinity)
