Macrophages and Dendritic Cells

The macrophage (mf) plays a critical role as an important effector cell of the innate immune system and as an activator of the adaptive response. This cell type plays a key tissue remodeling role during fetal organ development, scavenging the cells that are genetically programmed to die. In mice, a feature distinguishing fetal mf from adult cells is their high proliferative capacity, which may be due to their activation status (reviewed in: Muramatsu 1993).

In contrast to mf, dendritic cells (DC) lack phagocytic activity, but they have an extraordinary ability to stimulate naïve T cells and initiate primary immune responses. Importantly, DC induce different types of T cell immune responses depending on the type of original maturation signal; therefore, DC are key regulators of the immune response (Liu 2001). Very little is known about DC in the fetal period. Cells with a DC/mf morphology can be found in the yolk sac, prehematopoietic liver, and in the mesenchyme by 4 to 6 weeks of gestation (Holt and Jones 2000). Thereafter, these mostly MHC class II-negative mf appear in the thymic cortex, the marginal zones of lymphnodes (LN), splenic red pulp, and in the bone marrow (Holt and Jones 2000). DC have been cited as being present in the thymic rudiment by week 6 to 7 of gestation (Muramatsu 1993) and have subsequently been found in several tissues, including the intestine and epidermis. Monocytes, however, are the first cell type to appear in fetal circulation (Forestier et al. 1991).

Differentiation pathways leading to DC are complicated and controversial (Ardavin et al. 2001), yet the potent ability of DC to initiate immune responses has lead to extensive research in the past decade aimed at using DC as antigen presenting cells (APC) in vaccine trials or in immunotherapeutic anticancer treatments. This body of research indicates that GM-CSF, IL-4, IL-6, IL-7, TNF-a, LT, and LIF play important roles in DC differentiation and maturation, and that Flt3L is a required factor (Ardavin et al. 2001; Liu 2001). IL-4 has been shown to be a key cytokine for inducing DC from human monocytes, whereas IL-7 is essential in the differentiation of DC from early thymic lymphoid precursors (reviewed in: Ardavin et al. 2001). The growth and differentiation of monocytes and mf are tightly regulated by specific growth factors (e.g., IL-3, CSF-1, GM-CSF, IL-4, IL-13) and inhibitors (e.g., IFN-g, TGF-p, LIF) (Gordon 2003). MHC class II-positive mf appear in the liver by 7 to 8 weeks of gestation, in the LN at 11 to 13 weeks of gestation, and in the T-cell areas of the developing thymic medulla by 16 weeks of gestation. A few hepatic sinusoidal mf (Kupffer cells) are seen by 17 weeks of gestation and reach nearly adult levels in the neonatal period. Langerhans cells can be detected in the skin by 6 to 7 weeks of gestation and develop the larger and more dendritic adult morphology by the second trimester (Holt and Jones 2000).

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