Formation of the Immunoglobulin Repertoire in Precursor-B-cell Development

Precursor-B cells develop in bone marrow (BM) from hematopoietic stem cells (HSC) with the ultimate goal to generate mature B-cells with unique immunoglobulins (Ig), whereby all B cells together provide an enormous Ig repertoire diversity. Formation of the Ig occurs through somatic V(D)J recombination of the Ig heavy chain (IGH) and the Ig light chain (IGK or IGL) loci that contain multiple variable (V), diverse (D) and joining (J) coding elements. The Ig loci recombine in a ordered manner. The IGH locus rearranges before the Ig light chain loci and functional Ig rearrangements are generally restricted to one allele. Thus, the ordered accessibility of Ig loci for rearrangements is tightly controlled.

Studies described in this thesis aimed to better understand the mechanisms underlying the stage-specific regulation of V(D) J recombination and the generation of a diverse Ig repertoire during precursor-B-cell development. The stepwise V(D)J recombination process is controlled by transcriptional and epigenetic mechanisms which must cooperate together to provide the developmental increase in Ig loci accessibility for rearrangement. The formation of the broad Ig repertoire is dependent on the B-cell developmental niche. The BM niche undergoes physiological changes during life and therefore provides different signals to developing B cells, resulting in distinct Ig gene repertoires with distinct reactivity.

Future studies should reveal which environmental factors modify the Ig loci accessibility for the V(D)J recombinase and thereby control the Ig repertoire and reactivity. Such knowledge might be applicable for shaping the Ig repertoire in immune deficient patients.