B cell development - Clark Science Center · •B/T cells originate in bone marrow •Ag receptor...
Transcript of B cell development - Clark Science Center · •B/T cells originate in bone marrow •Ag receptor...
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B cell development
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T cell development
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Bone marrow stromal cellsprovide signals for growth
Adhesivecontacts
VLA-4:ICAM
Growth signalsSCF:Kit
IL-7
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Main steps in Bcell development
Heavy chain rearrangement
Heavy chain pairs withsurrogate light chain
Proliferation of pre-B cell
Light chain rearrangement
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Assuring productive Ig generearrangement
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Repeated rearrangement canoccur at light chain loci
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Negative selection of B cells
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Receptor editing
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B cells must enter lymphoidtissue to survive
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B cell population dynamics
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T cell development
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Similarities• B/T cells originate in
bone marrow• Ag receptor (TCR)
rearrangement• Negative selection
Differences• T cells develop in
thymus• Positive selection
required• Coreceptor expression
required (CD4 orCD8)
Comparison of B and T celldevelopment
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Importanceof thymusfor T celldevelopment
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Thymus structure
Cortex=+ selection
Medulla=- selection
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Basic overviewof T celldevelopment
+ selection
- selection
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Main T celldevelopmentalsteps
β chain rearrangement
pTα pairs with β= pre-T cell receptor
Proliferation andCD4/CD8expression
α chain rearrangement
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Repeated rearrangements of αchain
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Positive and negative selection
• Positive selection=– Retain T cells whose TCR can bind to MHC
• Negative selection=– Delete T cells whose TCR binds tightly to
MHC containing self peptide
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Thymus as site for positive andnegative selection
Thymic epithelialcells=substrate for +selection
APC=substrate for -selection
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Positive selection• Selection for TCRs
that recognizeMHC expressed
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CD4/CD8 choice driven by TCRinteraction with MHC and coreceptor
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Negativeselection:preventingautoimmunity
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Positive andnegativeselectioncannot
depend onsame signals
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Avidity hypothesis– Depends on strength of signal– Binding strength depends on:
• MHC:peptide complex• Density of complex on cortical cells
– T cells that bind to cortical cells are rescued fromapoptosis during positive selection
– T cells that bind tightly to APC are driven to apoptosis– Greater subset of TCRs are likely to bind weakly,
yielding T cells in the periphery
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Differential signaling hypothesis
— Nature of signal delivered, not their affinity— Depends primarily on peptides— Partial versus complete signal— MHC:peptides complexes that send partial signal allows
rescue from apoptosis during positive selection— MHC: peptides that send complete signal lead to apoptosis
during development
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Bone marrow transplants
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Matching MHC alleles in bonemarrow transplants
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Graft versus host disease(GVHD)
• severe inflammatory disease• acute GVHD=
– epithelial cell necrosis in skin, liver, GI tract• chronic GVHD=
– not as much necrosis, but atrophy of organs– unknown exactly how this occurs- may be scarring
after repair of necrosis• Due to mature T cells in graft
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The good and the bad of GVHD