Development Of The Fetal Immune System

Hematopoietic stem cells (HSC) are classically defined as those cells that: 1) give rise to the specialized cells of blood; and 2) have a capacity for extensive proliferation resulting in renewal of their own kind (Orkin and Zon 2002; Owen 1972). A bulk of information about hematopoiesis derives from the early 20th century (Tavassoli and Yoffey 1983), yet technological advances have since added to and called into question established developmental paradigms. Two modified paradigms are discussed here. First, historic studies concluded that HSC develop extraembry-onically in the yolk sac (Metcalf and Moore 1971; Migliaccio et al. 1986; Owen 1972; Tavassoli and Yoffey 1983) and then migrate to the fetal liver, bone marrow, and other sites. Recent reports from avian and mouse studies now indicate that HSC arise in the aorta-gonad-mesonephros (AGM) region (Godin et al. 1993; Jaffredo et al. 2000; Muller et al. 1994) (reviewed in: Kincade et al. 2002; Nishikawa et al. 2001). Whether this type of HSC derives originally from yolk sac HSC is unknown (Nishikawa et al. 2001; Orkin and Zon 2002), but this population is able to repopulate the hematopoietic cells in an irradiated adult mouse. Therefore, HSC from the AGM have been termed definitive HSC, as opposed to primitive HSC from the yolk sac that appear to persist only during embryonic life (Orkin and Zon 2002). A modern paradigm for hematopoiesis is described later in this chapter.

A second recent paradigm shift involves lineage commitment of the pluripotent cells developing from the HSC. HSC have been assumed to give rise to a common myeloid precursor (CMP) with erythroid potential and a common lymphoid precursor (CLP) that produces both B and T lymphocytes (Cooper et al. 1993). Recent findings by Kondo et al. support this traditional scheme (1997), but research by Katsura and colleagues makes use of a multilineage progenitor (MLP) assay to refute this idea (reviewed in: Katsura 2002; Kincade et al. 2002). Katsura's group suggests that the idea that T and B cells derive from a common progenitor developed because both T and B cells recognize antigens specifically with clonally distributed receptors, use a similar molecular apparatus to develop antigen-receptor genes, and are deficient in patients and mice with severe combined immunodeficiency (SCID) disease (Katsura 2002). However, similar use of genes (coopted perhaps from an evolutionary precursor) cannot argue for a common progenitor. Moreover, a definite answer can only come from an assay system permissive for the development of all cell lineages and utilizing purified progenitor cells. Katsura and colleagues provide evidence that T- and B-cell progenitors arise from differentiation of a common myelolymphoid progenitor through a bipotential myeloid/T and myeloid/B stage, respectively (Kawamoto et al. 1997). Their research implies that T and B cells are related more to myeloid cells than to each other (Kincade et al. 2002). Further research should elucidate whether fetal progenitors conform to a stepwise lineage-restriction program of development or have an inherent degree of plasticity, enabling them to generate the spectrum of cell lineages in response to environmental cues.

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