B Cell Biology (Affinity Maturation, Memory, Plasma Cell Homeostasis) Flashcards
Why are memory cells able to respond quickly?
proteins necessary for division (Cdks etc) are already synthesised
cells preloaded with effector molecules eg IFN-γ, TNF-α
elevated levels of signalling compounds and transcription factors (eg Lck in T cells)
higher frequency than naive cells (a 1000 fold increase)
higher Ab affinity (affinity maturation)
some are resident in tissues
epigenetic priming: effector genes are much more accessible eg e.g., histone acetylation, chromatin remodeling
Memory cells express higher levels of cytokine receptors, such as IL-7R and IL-15R
- makes them more sensitive to environment
What are some characteristics of memory B cells?
- express switched isotypes (some remain IgM+)
- express somatically mutated Ig V genes
- express higher affinity Ig
- lower activation thresholds
- increased levels of adhesion molecules (CD44, LFA-1) = improved interactions w APCs and increased recruitment to site of inflammation
plasma cells are not memory cells as they have finite lifespans
Why do memory T cells change the isoform of CD45 they express?
- naive resting T cells express high molecular weight forms of CD45 (RA, RB, and RC)
- lose expression of these after antigenic stimulation
– arise in differences with alternative splicing
– shorter isoform brings the phosphatase domain of CD45 closer to the TCR signaling complex
– Enhances the dephosphorylation of inhibitory sites on Lck , amplifying downstream signaling
= more efficient and rapid T cell activation in memory cells
– used as a marker for memory T cells, however reversion to RA, RB, or RC expression does occur
How does memory cell differentiation occur?
asymmetry occurs at a population level rather than a cellular level
ie populations exposed to different microenvironments diverge
low Ag +/- cytokines = memory
high Ag + cytokines = effector
What TFs are important for differentiation of CD8 into SLEC or memory cells?
Blimp1: induces activated T cell/early effector to become short lived effector cell (SLEC)
– expresses low IL-7R, important survival factor
Bcl6: induces activated T cell/early effector to become a memory precursor effector cell, continued exposure = memory cells
– actively downregulates Blipm1
What are the different types of B cell and what induces them?
short-lived plasma cells: Blimp1
germinal centre B cells: exposure of activated B cells to Bcl6
– these B cell produce Bcl6 for upkeep of germinal centre
long lived plasma cells: exposure of Blimp1 to gc B cells
memory B cells: arise from gc B cells
What are two populations of memory cells?
- those that differentiate and respond upond reinfection – effector memory
- those that renew memory pool
if all memory cell differentiated upon reinfection then the memory would be lost
T cell memory is impaired in mice without B cells.
experiments show that compared to WT mice, mice without B cells have a lower number of memory T cells after 12 weeks
How do B cells act as decoys to create memory T cells?
During T cell contraction, T cells express both Fas and FasL on their surface, clearing cells as they can cause each other to apoptose
B cells also express Fas, so can act as decoys to cause T cells to become memory in the germinal centre due to interactions w CD4
some B cells may be lost
this is hypothetical
How are memory B cells tracked in vivo?
phycoerythrin bins B220 memory B cells
How are memory T cells tracked in vivo?
MHC class II tetramers can bind to the T cell receptors (TCRs) of CD4+ T cells that specifically recognize the peptide-MHC complex
What is homeostatic regulation of lymphocytes?
all lymphocytes are under constant selective pressure as the size of the lymphoid system is controlled within strict limits
– if many lymphocytes are injected , the immune system does not incorporate them all
– after a couple of days it returns to its normal size
– there appear to be a finite number or niches in the immune system that lymphocytes can occupy
eg access to DCs and cytokines
once all niches are occupied, older memory cells are deleted
How do we know about lymphocytic survival niches?
when memory T cells (from TCR transgenic mice) are transferred into immunodeficient hosts (eg RAG -/- or SCID) the number of niches is not longer limiting
lifespans may be extended compared to that in a complete immune system
What are some factors influencing memory survival?
- antigen persistence (on FDC or other sites eg persistent viruses)
- re-exposure to priming agent (pathogen)
- exposure to a cross-reacting organism/antigen
- non-specific signals (cytokines)
oldest memory cells lose survival receptors eg IL-15R (homeostatic attrition)
Why does memory not equal protective immunity?
memory is an accelerated, enhance response
– may not give absolute protection from re-infection
protective immunity provides complete protection from re-infection
– provided by effector cells and tissue-resident effector memory cells
– dependent on antigen
How is measles an example of memory?
immunity to measles was long lived
- re-exposure to virus was not essential for long term protective immunity
not evidence for antigen free survival
- persists within the body (CNS)
How does the BCR signal?
BCR = membrane Immunoglobulin (mIg)
signalling heterodimer composed of Igalpha and Igbeta subunits (CD79a and CD70b)
Both have ITAMs in their cytoplasmic tails
When an antigen binds to the BCR:
receptor cross-linking occurs, bringing multiple BCRs together on the membran
This clustering brings Igα/Igβ molecules into close proximity, facilitating their phosphorylation by
Src-family kinases (e.g., Lyn, Fyn, or Blk) which phosphorylate the ITAMs
Phosphorylated ITAMs act as docking sites for downstream signaling molecules eg Syk
What is the structure of the B cell surrogate light chain?
composed of two non-polymorphic proteins:
- VpreB: mimics variable region of Ig light chain
- λ5: mimics constant region of Ig light chain
these two proteins pair w a successfully rearranged Ig heavy chain (igH) to form the pre-BCR
