B cell development

T cell development

Bone marrow stromal cellsprovide signals for growth

Adhesivecontacts

VLA-4:ICAM

Growth signalsSCF:Kit

IL-7

Main steps in Bcell development

Heavy chain rearrangement

Heavy chain pairs withsurrogate light chain

Proliferation of pre-B cell

Light chain rearrangement

Assuring productive Ig generearrangement

Repeated rearrangement canoccur at light chain loci

Negative selection of B cells

Receptor editing

B cells must enter lymphoidtissue to survive

B cell population dynamics

T cell development

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

Importanceof thymusfor T celldevelopment

Thymus structure

Cortex=+ selection

Medulla=- selection

Basic overviewof T celldevelopment

+ selection

- selection

Main T celldevelopmentalsteps

β chain rearrangement

pTα pairs with β= pre-T cell receptor

Proliferation andCD4/CD8expression

α chain rearrangement

Repeated rearrangements of αchain

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

Thymus as site for positive andnegative selection

Thymic epithelialcells=substrate for +selection

APC=substrate for -selection

Positive selection• Selection for TCRs

that recognizeMHC expressed

CD4/CD8 choice driven by TCRinteraction with MHC and coreceptor

Negativeselection:preventingautoimmunity

Positive andnegativeselectioncannot

depend onsame signals

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

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

Bone marrow transplants

Matching MHC alleles in bonemarrow transplants

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

The good and the bad of GVHD