The production of lymphocyte progenitors from the multipotent progenitor cell is accompanied by expression of the receptor for interleukin-7 (IL-7), which is induced by FLT3 signaling together with the activity of PU.1. The cytokine IL-7, secreted by bone marrow stromal cells, is essential for the growth and survival of developing B cells in mice (but possibly not in humans). The IL-7 receptor is composed of two polypeptides, the IL-7 receptor α chain and the common cytokine receptor γ chain (γ-c), so called because it is also a subunit of five additional cytokine receptors. This family of cytokine receptors includes the receptors for IL-2, IL-4, IL-9, IL-15, and IL-21, in addition to IL-7. These receptors also share the tyrosine kinase Jak3, a signaling protein that binds exclusively to γ-c and is required for productive signaling by each of the receptors.
Due to the importance of IL-7 for murine B-cell development, mice with a genetic deficiency in IL-7, IL-7 receptor α, γ-c, or Jak3 all exhibit a severe block in B-cell development.
Another essential factor for B-cell development is stem-cell factor (SCF), a membrane-bound cytokine present on bone marrow stromal cells that stimulates the growth of hematopoietic stem cells and the earliest B-lineage progenitors. SCF interacts with the receptor tyrosine kinase Kit on the precursor cells (see Fig. 8.3). The chemokine CXCL12 (stromal cell-derived factor 1, SDF-1) is also essential for the early stages of B-cell development. It is produced constitutively by bone marrow stromal cells, and one of its roles may be to retain developing B-cell precursors in the marrow microenvironment. Thymic stroma-derived lymphopoietin (TSLP) resembles IL-7 and binds a receptor that includes the IL-7 receptor αchain, but not γ-c. Despite its name, TSLP may promote B-cell development in the embryonic liver and, in the perinatal period at least, in the mouse bone marrow.
A definitive B-cell stage, the pro-B cell, is specified by induction of the B-lineage-specific transcription factor E2A. It is not clear what initiates the expression of E2A in some progenitors, but it is known that the transcription factors PU.1 and Ikaros are required for E2A expression. E2A then induces the expression of the early B-cell factor (EBF). IL-7 signaling promotes the survival of these committed progenitors, while E2A and EBF act together to drive the expression of proteins that determine the pro-B-cell state.
As B-lineage cells mature, they migrate within the marrow, remaining in contact with the stromal cells. The earliest stem cells lie in a region called the endosteum, which lines the inner cavity of the long bones such as the femur and tibia. Developing B-lineage cells make contact with reticular stromal cells in the trabecular spaces, and as they mature they move toward the central sinus of the marrow cavity. The final stages of development of immature B cells into mature B cells occur in peripheral lymphoid organs such as the spleen, which we describe in Sections 8-7 and 8-8 of this chapter.
8-2 B-cell development begins by rearrangement of the heavy-chain locus.