L20- Lymphocyte activation Flashcards
How does the humoural immune response occur (steps)?
- Antigen recognition by B/T cell receptors
- Lymphocyte activation- differentiation, clonal expansion
- Antigen elimination
- Contraction (homeostasis)- apoptosis
- Memory
What is the structure of the BCR complex?
- Membrane bound immunoglobulin and dimer of CD79A and B
- CD79A and B signal and enable transport of receptor complex to and from cell surface
- Signalling occurs via phosphorylation of ITAMS
What is the structure of the TCR complex?
- Ig superfamily
- Complex with CD3 and CD247
- Associated proteins signal and facilitate transfer to the cell surface
- More complex with more components and ITAMs than BCR
What are the principles (steps) of receptor signalling?
- Receptor associated kinases inactive and adaptor has SH2 domains
- Ligand binds and activates kinase. Kinase phosphorylates ITAMs on receptor
- Phosphorylated ITAMs recruits adaptor via SH2
- Adaptor recruits secondary messengers like kinases, PLC-g and G protein exchange factors
How is BCR signalling initiated?
- In resting B cells BCR associates weakly with three Src family kinases Blk, Fyn and Lyn.
- BCR crosslinking by antigen activates Blk, Fyn and/or Lyn.
- Src family kinases phosphorylate tyrosine residues in the ITAMs of CD79A/B.
- ITAM phosphorylation recruits Syk via its 2 SH2 domains.
- Clustered BCRs bring about Syk activation by trans-phosphorylation.
How is BCR signalling propagated?
- Syk phosphorylates multiple sites on scaffold adaptor protein BLNK
- BLNK phosphorylation recruits and activates BTK, G protein exchange factors and PLC-g
- Breaks down PIP2 to IP3 and DAG
What do GEFs and IP3 and DAG do?
- IP3 induces release of Ca2+ from ER and increases intracelullar calcium
- This activates NFAT
- DAG and Ca2+ activate NF-KB pathway
- GEFS activate MAPK kinase to induce AP-1
What do NF-KB, NFAT and AP-1 do?
They work together to induce gene transcription that leads to proliferation and activation of lymphocytes
How is TCR signalling initiated?
- Recognition of MHC by co-receptors- CD4 and CD8
- Lck brought to TCR
- Lck phosphorylates ITAMs on zeta chain and CD3
- Phosphorylated ITAMs reccruit ZAP-70 tyrosine kinase
How is TCR signalling propagated?
- Activated ZAP-70 phosphorylates LAT and SLP-76
- SLP-76 activates PLC-g which cleaves PIP2 to DAG and IP3
- Same pathway as BCR
What are the signals required for T cell activation?
- Specific receptor-ligand interaction activates cell (TCR-MHC-PEPTIDE)
- Co-stimulation via APC surface molecules e.g CD28/B7- promotes cell survival
- Cytokines direct the differentiation of T cell effector functions- instructional
What is an immune synapse?
It integrates antigen receptors, co- stimulatory receptors and adhesion molecules
How is an immune synapse formed?
- Antigen receptors move to centre of synapse
- BCR/TCR signalling activates adhesion molecules and upregulates co-stimulatory molecules
- Adhesion molecules are in proximal ring and stabilise synapse
- Inhibitory molecules are in the distant ring
What are the advantages of immune synapses?
- Stabilises cell-cell contact to allow more receptors to bind to their ligands
- Increased stability facilitates signalling by lower affinity antigens
- Directed secretion of cytokines in synapse
What happens to T cells that recognise antigens without co-stimulation?
• Differentiation into Tregs or become anergic (unresponsive) to prevent activation by ‘self’
What two functions does the BCR serve?
- Detects external antigen and activates the B cell
2. Captures external antigen to express on the cell surface in MHCII
What is thymus-dependent B cell activation?
- When B cell receives second signal from a Th cell that recognises the same antigen (cognate T cell)
- Minimises autoimmunity because both B/T cells must survive deletion
- Cognate B/T cells recognise different parts of same antigen- linked recognition
What is thymus independent B cell activation?
• No need for T cell help
What are type 1 and type 2 independent antigens?
Type 1: activate the BCR and other receptors
Type 2: crosslink the BCR with repeating epitopes
What are the consequences of activation?
- Cells proliferate
* Cells differentiate into different cell types e.g plasma. memory, CD4+, CD8+
What is a germinal centre?
When cognate B/T cells meet and form germinal centre where rapid clonal expansion and affinity maturation by somatic hypermutation and class switching occurs
What happens if too much BCR signalling occurs?
• Mutations in ITAMS of CD79A/B result in antigen independent signalling and aggressive diffuse large B cell lymphoma
