Richard R Hardy, PhD
Office Phone: 215-728-2469
Lab Phone: 215-728-2463
Fetal and Adult B Lymphocyte Differentiation
B lymphocyte development in mouse, as in humans, takes place in the fetal liver before birth and shifts shortly thereafter to the bone marrow, where it continues throughout life. The generation of B cells is a highly ordered process, orchestrated by a number of transcription factors that regulate expression of a set of lymphoid and B lineage specific genes at well-defined developmental stages. During this process, immunoglobulin (Ig) heavy chain D-to-J rearrangements in pro-B cells precede V-to-DJ rearrangements that eventually yield functional heavy chain protein in pre-B cells. In pre-B cells, this Ig heavy chain protein associates with B lineage specific surrogate light chain components to form a pre-BCR. This signals events required for development to later stages where Ig light chain rearrangement takes place and is expressed. Ig light chain becomes associated with heavy chain, allowing a complete Ig molecule, the BCR, to be expressed on the surface of a newly formed B cell.
The interests of my laboratory focus on three areas related to this process: 1) elucidating the stage(s) and molecular/cellular interactions taking place as B cell precursors become progressively restricted to the B lineage; 2) determining the role of Ig heavy chain VDJ structures in guiding B cell development; and 3) comparing fetal and adult B cell development, particularly as related to the preferential generation of autoreactive malignant-prone CD5+ ("B-1") B cells during embryogenesis. We utilize transgenesis and knockout/knockin mice to study these issues. We are also investigating the peripheral maturation of B cells in spleen and have initiated a project to mark B cells in the zebrafish. Recently we have identified the transcription factor Arid3a as key in mediating fetal B cell development. We are now studying whether this fetal versus adult B cell developmental switch also occurs in humans, and have generate preliminary data suggesting that it does.