Lymphocyte Maturation & Receptor Diversity

Lymphocyte Maturation & Receptor Diversity

1. General features

   • Definition
     • The process of progenitors converting to mature lymphocytes
   • Maturation stages
     • 1. Early maturation
     • 2. Expression of Ag receptor genes
     • 3. Mature repertoire selection
   • Maturation checkpoints
     • To ensure only lymphocytes with antigen receptor gene will be selected.
     • During pre-stage: At least a single-chain Ag receptor produced for survival
     • At immature stage: Both Ag receptor chains must be produced
   • Selection
     • Positive selection
       • Check T cells are able to interact with MHC molecules
       • Check B cells which weakly bind to self Ags
     • Negative selection
       • Deletes lymphocyte that binds strongly to self Ags.

2. Germline Organization

   • Organization
     • Characterised by spatial segregation of multiple sequences that encode variable and constant domains of receptor protein
     • V domain in Ig chain protein
       • L chain: V and J gene segments
       • H chain: V, D and J gene segments
   • Somatic recombination
     • Rearrangement of DNA (VDJ gene segment)
       • generates various combinations randomly
         • causes diverse Ag receptor specificities!
     • Process
       • Selecting one V, J & D gene each
         • forms single V(D)J gene
           • code for V region of Ag receptor protein
   • Generation of repertoires
     • Genetic mech. that cause B/T cell ag receptor diversity
       • Combinatorial diversity
       • Junctional diversity
     • Expression of Ag receptors: actual expression < theoretical maximum
       • Not all recombinations are equally likely to occur
       • Not all chain pairings form functional Ag receptors

3. Maturation of B cells

   • Stages
     • 1. Ig genes rearrangement & expression
     • 2. Immature cells proliferation
     • 3. Repertoire selection
   • H & L chain recombination & exp.
     • 1. H chain: 1D + 1J gene
       • 2. One 5'V gene + DJ complex
   • B cells development
     • Pre-B cells
       • Cytoplasmic μ H chain
         • Cannot recognize Ag
       • Pre-B cell receptor
         • Allelic exclusions
           • IMPORTANT! to maintain clonal specificity
             • to ensure single receptor expression
     • Immature B cell
       • Rearrangement of K or lambda L chain
         • Produce L chain that associates with μ chain
           • Complete IgM
     • Mature B cell
       • Co-exp. of IgM & IgD
         • same VDJ exon & same K and lambda L chain
       • Naive mature cells: Responsive to Ag
       • Found in
         • circulation
         • peripheral lymphoid organs

4. Activation of B cells

   • Recognition phase
   • Activation phase
   • Key roles of B lymphocyte Ag receptor in B-cell activation
     • Receptor binds to Ag
       • Ag-induced cluster of receptors deliver biochemical signals
         • B-cell activation
       • Ag is protein, B-cell becomes APC
   • B-cell antigen receptor complex
     • Ig-mediated cells transduced by Igα & Igβ
       • Cytoplasmic domains of Igα & Igβ contain tyrosine-rich motifs (ITAMs)

5. Second Signal Activation by Complement Receptors

   • 2nd signal
     • C3d
       • bind to B cell receptor: CR2, CD21
   • Function
     • Ensure B cell respond to Ag/microbe that activated complement
     • Provides amplification mech. for humoral immunity

6. B cell Activation

   • Induced by: Protein Ags
     • T-cell dependent
   • Induced by: Multivalent Ags
     • T-Cell Independent (TI)
       • Properties
         • Non-protein antigens
           • Polysaccharides
           • Glycolipids
           • Nucleic acids
         • Cannot process/present with MHC molecules
           • CD4+ T helper cell cannot recognize
         • Multivalent
           • Composed of repeated identical antigenic epitopes
           • Induce maximal cross-linking
           • Activate without requirement for cognate T cell help
       • Antibody produced
         • Low affinity
         • Mainly IgM
           • Limited isotype switching
           • To some IgA and IgG subtypes
         • Produced in absence of T cell

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