Fig. 8.2 A multipotent hematopoietic stem cell generates all the cells of the immune system. In the bone marrow or other hematopoietic sites, the multipotent stem cell gives rise to cells with progressively more limited potential. A simplified progression is shown here. The multipotent progenitor (MPP), for example, has lost its stem-cell properties. The first branch leads to cells with myeloid and erythroid potential, on the one hand (CMPs and MEPs), and, on the other, to the common lymphoid progenitors (CLPs), with lymphoid potential. The former give rise to all nonlymphoid cellular blood elements, including circulating monocytes and granulocytes, as well as the macrophages and dendritic cells that reside in tissues and peripheral lymphoid organs (not shown). The CLP population is heterogeneous and single cells can give rise to NK cells, T cells, or B cells through successive stages of differentiation in either the bone marrow or thymus. There may be considerable plasticity in these pathways, in that in certain circumstances progenitor cells may switch their commitment. For example, a progenitor cell may give rise to either B cells or macrophages; however, for simplicity these alternative pathways are not shown. Some dendritic cells are also thought to be derived from the lymphoid progenitor.
Fig. 8.3 The early stages of B-cell development are dependent on bone marrow stromal cells. Interaction of B-cell progenitors with bone marrow stromal cells is required for development to the immature B-cell stage. The designations pro-B cell and pre-B cell refer to defined phases of B-cell development, as described in Fig. 8.4. Multipotent progenitor cells express the receptor tyrosine kinase FLT3, which binds to its ligand on stromal cells. Signaling through FLT3 is required for differentiation to the next stage, the common lymphoid progenitor. The chemokine CXCL12 (SDF-1) acts to retain stem cells and lymphoid progenitors at appropriate stromal cells in the bone marrow. The receptor for interleukin-7 (IL-7) is present at this stage, and IL-7 produced by stromal cells is required for the development of B-lineage cells. Progenitor cells bind to the adhesion molecule VCAM-1 on stromal cells through the integrin VLA-4 and also interact through other cell-adhesion molecules (CAMs). The adhesive interactions promote the binding of the receptor tyrosine kinase Kit (CD117) on the surface of the pro-B cell to stem-cell factor (SCF) on the stromal cell, which activates the kinase and induces the proliferation of B-cell progenitors. The actions of the listed transcription factors in B-cell development are discussed in the text. The pink horizontal bands denote the expression of particular proteins at the indicated stages of development.
receptors that are required for the development of multiple hematopoietic lineages, such as the transcription factor PU.1 and the receptor c-kit. In the next stage, MPPs produce two subsets of progenitor cells that give rise to all the lymphocyte lineages. One progenitor cell, as yet unnamed, produces the ILC subsets, ILC1, ILC2, and ILC3 cells. A second progenitor cell arising from the MPP is known as the common lymphoid progenitor (CLP). Differentiation of MPPs into CLPs requires signaling through the FLT3 receptor expressed on MPPs. Progenitor cell transfer and lineage repopulation experiments have shown that the CLP population is actually heterogeneous and represents a continuum of cells with decreasing multipotent potential. A subset of CLP cells with the broadest potential is able to generate B cells, T cells, and NK cells. A second subset of CLPs is able to generate only B cells and T cells, and a third subset of CLPs is committed exclusively to the B-cell lineage. B-cell-committed CLPs give rise to pro-B cells (see Fig. 8.3).