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- Production of new lymphocytes (lymphopoiesis): in central lymphoid
tissues
- B cells: bone marrow; fetus (fetal liver, yolk sac)
- T cells: precursor cells in bone marrow and then migrate to thymus
- Ag specificity of an individual lymphocyte is determined early in its
differentiation by gene rearrangement. The early stages of B and T cell
development proceed along broadly similar lines.
- Specificity and affinity of the receptors determine the fate of the
immature lymphocytes
- -Positive selection: interact weakly with self Ag. Receive signals to
survive. Eg. α:β T cells recognize peptide bound to MHC
- -Negative selection: lymphocytes whose receptors bind strongly or not
at all to self antigen and receive signals to die (immunological
tolerance).
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5
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6
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- The stages of B cell development and VDJ recombination
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- Btk: Bruton’s tyrosine kinase. Mutation causes a profound B-lineage
specific immune deficiency (Bruton’s X-linked agammaglobulinemia, XLA)
in which no mature B-cells are produced.
- Mouse equivalent (xid) more “leaky”; some mature B cells get by pre-B
block, but they are signaling compromised as well.
- Tec family tryrosine kinase regulated via PKC, Ca2+ pathway (Chapter 6);
- Mutations in plextrin homology domain (PHD)
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- Gene rearrangement: Comparison in B cell and T cell
- SIMILARITIES
- T cells have almost identical strategies as B cells
- Use the same enzymes
- Light chain ↔ TCRα(V, J) ; Heavy chain ↔ TCRß (V, D, J)
- One productively rearranged VDJ is expressed with surrogate chain(s) as
soon as it is made
- The mature receptor is required for further development and shutting
down further rearrangement
- DIFFERENCES
- Three separate lineages of T cells: α:ß, γ:δ, and α:ß-NK
- Non productive ß-chain VDJ can be rescued by subsequent rearrangement
because of two clusters of Dß and Jß upstream of
two Cß
- The chances are higher for productive rearrangement of ß chain that for
Ig heavy chain.
- B cells: Final assembly of an immunoglobulin leads to the cessation of
gene rearrangement and initiates further differentiation
- T cells: rearrangement of V α continues until
positive selection by self-peptide: self-MHC complex
- RAGs are transcriptionally regulated by different enhancers and V
segments loci are differentially accessible at chromatin level.
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- Pre-T cell receptor (pTα:ß) , analogous to pre-B cell receptor
(µ:VpreB:λ5), forms a complex with CD3
- triggers the phosphorylation and degradation of RAG2è Halting ß chain rearrangement
and ensure allelic exclusion
- Induces cell proliferation and the expression of co-receptors, CD4 and
CD8
- This event is dependent on Lck
- First α chain rearrangement delete δ genes
- Productive α chain is paired with ß chain è DP CD3low selection for its ability to recognize self
peptides with self MHC
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