Germinal Centre Flashcards
Where do germinal centres arise?
secondary lymphoid organs including the lymph and spleen
What does the GC cortex contain?
B cell follicles
What does the paracortex contain?
The T cell zone
What result would we want from a productive GC reaction?
1) Plasma cells = short lived, produce large amount of high affinity antibodies
2) Memory b cells = can differentiate into plasma cells upon antigen re challenge
What are some examples of B cells in the GC?
1) centroblasts: rapidly proliferate, undergo somatic hypermutation of their Ig to create diverse antibodies
2) memory b cells = launch a faster response to antigens
3) B cells that differentiate to become plasma cells = more antibodies
What is the role of t follicular helper cells?
help B cells produce high affinity, class switched antibodies
What do follicular dendritic cells do?
present antigens to B cells -> display antigens in the form of immune complexes so B cells can test their new receptors for affinity
What do dendritic cells do?
present antigens to T cells in complex with MHC class II = activate naive T cells
What transcription factor do Tfh cells express and why is this important
Bcl-6 = bcl-6 controls the expression of CXCR5 which guides tfh cells to migrate into b cell follicles
What are the steps in the GC?
1) dendritic cell with antigen + naive T cell = tfh cell
2) activation of b cell by tfh
3) b cell proliferates and mutation occurs, GC expands,
4) b cells go from dark zone -> light zone and undergo selection
5) mutated b cells come in contact with FDC
6) memory cells and activation
What is the primary function of the immunological synapse?
to ensure effective and sustained T cell activation
What is the spreading phase in an immunological synapse?
1) after contact with a T cell and and APC, the T cell undergoes spreading to maximise area of contact with APC
2) involves actin polymerisation = allows T cell to flatten out over the surface of the APC.
3)TCR microclusters form between the two cells -> microclusters contain CD28 and initiates early signalling cascade
What is the contraction phase of an immunological synapse?
1) reorganisation of the cytoskeleton and pulling back of the contact area, concentrating the interactions between T cell and APC
2) TCR microclusters move towards centre of the interface -> into the central supramolecular activation cluster
3)forms a more stable and mature immunological synapse
What happens within the cSMAC?
- TCR-MHC interactions are maintained and CD28 bind to their ligands on the APC
Why is ICOS important in Tfh cell differentiation?
- binding of ICOS to its ligand ICOS-L provides a critical signal for Tfh cell differentiation
-upregulates Bcl-6 (required for Tfh differentiation)
-induces CXCR5- without ICOS Tfh cannot migrate to follicles where germinal centres form
Why is IL-21 important in Tfh cell differentiation?
1)helps stabilise the expression of BCL-6
2)promotes expansion and survival of Tfh cells
3) supports B cell proliferation, somatic hypermutation -> leads to production of high affinity antibodies
How does GC seeding occur?
1) activated b cells present antigens via MHC II molecules on their surface
2) they then move to the T-B border where they encounter Tfh cells
3) after contact between b cells and tfh cells -> co stimulatory signals are delivered
4) after receiving these signals the b cells undergo proliferation and either become plasma cell/ migrate into the follicle
5) b cells proliferate and create GC structure
What occurs in the dark zone?
proliferating B cells (centroblasts) undergo somatic hypermutation in their Ig genes -> point mutations in the variable regions of the BCR generates B cells with varying affinities for the antigen
What occurs in the light zone?
mutated b cells (centrocytes) migrate to the light zone where they compete for survival signals based on the affinity of their newly mutated BCRs
What is selection and affinity maturation in regards to the light zone?
1) B cells that bind antigen with high affinity are selected to undergo further proliferation
2) low affinity B cells that fail to compete for antigen and Tfh undergo apoptosis
What happens to successful B cells in the light zone?
they re-enter the dark zone to undergo additional rounds of proliferation and somatic hypermutation -> increases affinity more
What role does CXCR4 play in migration to the light zone?
1) in the dark zone CXCR4 interacts with CXCL12 = keeps b cells in dark zone
2) CXCR4 is down regulated which makes B cells less responsive to CXCL12
3) CXCL13 is the ligand for CXCR5 -> guides B cells to the light zone for selection
Which cells secrete CXCL12?
cortical reticular cells
Which cells secrete CXCL13?
Follicular dendritic cells
