At each step of lymphocyte development, the progress of gene rearrangement is monitored; the major recurring theme is that successful gene rearrangement leads to the production of a protein chain that serves as a signal for the cell to progress to the next stage. We will see that a developing B cell is presented with opportunities for multiple rearrangements that increase the likelihood of expressing a functional antigen receptor, but that there are also checkpoints that reinforce the requirement that each B cell express just one receptor specificity. We will start by looking at how the earliest recognizable cells of the B-cell lineage develop from the multipotent hematopoietic stem cells in the bone marrow, and at what point the B-cell and T-cell lineages diverge.
8-1 Lymphocytes derive from hematopoietic stem cells in the bone marrow.
The cells of the lymphoid lineage—B cells, T cells, and innate lymphoid cells (ILCs)—are all derived from common lymphoid progenitor cells, which themselves derive from the multipotent hematopoietic stem cells (HSCs) that give rise to all blood cells (see Fig. 1.3). Development from the precursor stem cell into cells that are committed to becoming B cells or T cells follows the basic principles of cell differentiation. Properties that are essential for the function of the mature cell are gradually acquired, along with the loss of properties that are more characteristic of the immature cell. In the case of lymphocyte development, cells become committed first to the lymphoid lineage, as opposed to the myeloid, and then to either the B-cell or the T-cell lineage (Fig. 8.2).
The specialized microenvironment of the bone marrow provides signals both for the development of lymphocyte progenitors from hematopoietic stem cells and for the subsequent differentiation of B cells. Such signals act on the developing lymphocytes to switch on key genes that direct the developmental program and are produced by the network of specialized nonlymphoid connective tissue stromal cells that are in intimate contact with the developing lymphocytes (Fig. 8.3). The contribution of the stromal cells is twofold. First, they form specific adhesive contacts with the developing lymphocytes by interactions between cell-adhesion molecules and their ligands. Second, they provide soluble and membrane-bound cytokines and chemokines that control lymphocyte differentiation and proliferation.
The hematopoietic stem cells first differentiate into multipotent progenitor cells (MPPs), which can produce both lymphoid and myeloid cells but are no longer self-renewing stem cells. Multipotent progenitors express a cell-surface receptor tyrosine kinase known as FLT3 that binds the membrane-bound FLT3 ligand on stromal cells. Additionally, MPPs express transcription factors and