Early morphological studies and, more recently, in vitro culture studies of murine embryonic stem cells support the existence of a bipotential hematopoietic-vascular precursor, i.e., the hemangioblast (reviewed in: Orkin and Zon 2002; Tavassoli and Yoffey 1983). The parallel development of endothelium and hematopoietic precursors foreshadows the significant future role played by the microenvironment in development of hematopoietic lineages.

In the bone marrow, stromal cells provide physical support as well as the growth factors and hormones important for the initiation of differentiation programs that produce the many cell lineages found there (reviewed in: Chaplin 2003). Particularly significant for immune function is the development of natural killer (NK) cells, B lymphocytes, dendritic cells, and macrophages (Muramatsu 1993) in the bone marrow compartment. Moreover, precursors of T lymphocytes originate in the bone marrow but emigrate to the thymus for further differentiation.

Like the bone marrow, the thymus also regulates the microenvironment ensuring proliferation and maturation of its resident hematopoietic cells. Unlike the bone marrow, the thymus also regulates the entry and maturation of hematopoietic cells to those that will function as T cells in the periphery (reviewed in: Chaplin 2003). The thymic stroma forms in the 6th week of gestation and divides into cortex and medulla by 10 to 12 weeks (Loke 1978). The medulla itself starts to develop around 14 weeks of gestation, and although thymocytes populate the thymus at approximately week 9 postconception (von Gaudecker 1991), the thymic medulla is not fully formed until week 17 (Kendall 1991).

The development of the thymus, while essential for maturation of most T cells, in turn requires population by T cells (Boyd et al. 1993; Kendall 1991) (reviewed in: Chaplin 2003). Moreover, it should be noted that the thymic microenvironment is under direct influences of the hypothalamus/pituitary axis. Furthermore, the central nervous system exerts control over the thymus through neural pathways (Boyd et al. 1993; Kendall 1991). The complexity of the T cell maturation environment underscores the contention that T cell development is not purely a genetically ordered event but can be significantly affected by other systemic regulatory systems.

The anatomic features of secondary lymphoid organs develop concomitantly with the central lymphoid organs in the fetus. Gut-associated lymphoid tissue (GALT) can be identified at week 8 of gestation; the lamina propria develops during weeks 8 to 10, followed by the occurrence of Peyer's patches and maturation of the appendix from 11-15 weeks postconception. Lymph nodes (LN) also appear from 8 to 12 weeks of gestation, followed by tonsils (and spleen, as mentioned previously) at 10 to 14

weeks (West 2002). The signals leading to the establishment and maintenance of the secondary lymph organs are not well defined, but IL-7 (interleukin-7), lymphotoxin (LT), and tumor necrosis factor (TNF) are known among these factors to play a critical role (reviewed in: Chaplin 2003; Mestecky et al. 2003). Other, less well-defined clusters of lymphoid and hematopoietic cells associated with the genitourinary, gastrointestinal, and respiratory tracts also contribute to host defense, but the origins and development of these systems are not clearly understood (Chaplin 2003).

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