2.2.1. Epithelial/Mesenchymal Interactions
The essential role of NCC in thymus organogenesis was demonstrated by the perturbed development of TEC in E12.5 thymic lobes cultured in the absence of the mesenchymal capsule (87). In addition, ablation of the migratory capacity of NCC, by artificially induced lesions in chick embryos (88) results in thymic aplasia or hypoplasia. However, although NCC are likely to be important in early stages of thymus formation, no functional role has been demonstrated before E12.5. Thymic NCC are not unique in their ability to support thymus organogenesis, as illustrated by experiments in which thymic epithelial rudiments from E12.5 mouse embryos were cultured with mesenchyme from non-thymic sources, including kidney and lung (87). This study demonstrated that nonthymic mesenchymal cells could support the development of the thymic epithelium, albeit not as effectively as pharyngeal NCC (87), and the chick-quail chimera study described above also indicated that the pharyngeal endoderm can induce nonpharyngeal mesenchyme to contribute to the thymus (71). Thus, during the initiation of thymus organogenesis, NCC mesenchyme may respond to patterning signals from the pharyngeal endoderm and then contribute to the development of the epithelial component of the thymus.
The mechanism by which mesenchymal cells influence thymus organogenesis is at least in part via the provision of soluble growth factors; Auerbach and colleagues demonstrated that the effects mediated by mesenchymal cells on the thymic epithelium could occur independently of cell-cell contact (87). In addition, the growth factors Fgf7 and Fgf10 are expressed by the mesenchymal cells surrounding the thymus, and TEC express their receptor, fibroblast growth factor receptor 2 Illb (FgfR2IIIb). FgfR2IIIb/- mice display a block in the growth of the thymic epithelium from E12.5, indicating that these factors play an important role during the development of the thymus (89). It has also been shown that insulin-like growth factor 1 (IGF-1) and epidermal growth factor (EGF) can support the in vitro growth and differentiation of E12.5 thymic lobes in the absence of the mesenchymal capsule (90) although the significance of IGF-1 and EGF in normal thymus development remains to be determined.
The requirement of lympho-stromal cross-talk for the expansion and maintenance of both cortical and medullary compartments is well established and has been reviewed extensively elsewhere (73,91,92). It is now clear that lympho-epithelial interactions are not required for initial epithelial differentiation, because the differentiation and patterning of the epithelium during embryonic development occurs normally until E15.5 in the absence of lymphoid cells committed to the T-cell lineage (67). Furthermore, TEC that differentiate in the absence of developing thymocytes retain their functional capacity (68). However, in the absence of thymocytes, the postnatal thymus is characterised by predominance of K5+K8+ cells and a reduction in epithelial cell number (67). This suggests that lympho-epithelial cross-talk is required for maturation/ expansion/maintenance of the cortical and medullary epithelial compartments and that, in the absence of cross-talk, immature TEC may revert to a TEPC phe-notype or TEPC-like cells may persist at the expense of more differentiated TEC. Because the aberrant thymic epithelial phenotype associated with secondary effects is reversible in some models, at least some of these cells must retain thymic epithelial identity rather than adopting aberrant fates.
The dialog between TEC and developing thymocytes is likely to involve both soluble factors and intercellular adhesion molecules. Thus, several cell adhesion molecules and cytokines and their receptors are reciprocally expressed by TEC
Fig. 4. Molecular regulation of early thymus development. (A) Tbxl expression (pink) is required in the pharyngeal endoderm (168) prior to E8.5 for formation of the third pharyngeal pouch (3pp). (B) E9.5—continued development of the 3pp is dependent on Fgf8, RA, Hoxa3, Pax1, Pax9, Eya1, and Six1, all of which are expressed in the endoderm (blue). Hoxa3, Eyal, and Sixl are also expressed in the pharyngeal arch mes-enchyme (gold), whereas the ectoderm of the third pharyngeal cleft (3pc) expresses Fgf8, Hoxa3, Eyal, and Sixl (green). The tissue specific requirements for these factors have not been elucidated. (C) E10.5—the dorsal opening of the 3pp expresses Shh
Fig. 4. Molecular regulation of early thymus development. (A) Tbxl expression (pink) is required in the pharyngeal endoderm (168) prior to E8.5 for formation of the third pharyngeal pouch (3pp). (B) E9.5—continued development of the 3pp is dependent on Fgf8, RA, Hoxa3, Pax1, Pax9, Eya1, and Six1, all of which are expressed in the endoderm (blue). Hoxa3, Eyal, and Sixl are also expressed in the pharyngeal arch mes-enchyme (gold), whereas the ectoderm of the third pharyngeal cleft (3pc) expresses Fgf8, Hoxa3, Eyal, and Sixl (green). The tissue specific requirements for these factors have not been elucidated. (C) E10.5—the dorsal opening of the 3pp expresses Shh and thymocytes. Examples include the adhesion molecules CD2 and CD58, CD54 and CD11a (92) and the cytokines IL-1, IL-4, IL-6, IL-7, and tumor necrosis factor a (31,93-104). In addition, certain subpopulations of thymocytes have been shown to express Fgf7 (105), a factor shown to be important in the growth and differentiation of the epithelium (89,105,106) although, as discussed previously, thymocytes are not the exclusive source of this growth factor.
Lymphotoxin P receptor (LTPR) and its ligands lymphotoxin P (LTP) and LIGHT were recently shown to have an important role in the maintenance of the thymic architecture (53,55). Expression of LTPR is found on mTEC, whereas LTP is expressed by medullary thymocytes (53). Mice lacking functional LTPR display a reduction in the number of mTEC, with those cells that persist existing as small isolated clusters instead of the organized network of epithelial cells typical of a normal medulla (53). Both LTP and LTPR deficient mice exhibit down-regulation of Aire expression in mTEC and develop autoimmune diseases (55), further indicating that this pathway is involved in the correct development of the medulla. In addition, the medulla of LTPR-/- mice retains increased numbers of mature CD4+ and CD8+ thymocytes, which themselves display upregulated expression of LTP (53). Thus, the LTPR-LTP interaction may operate in a regulatory loop and have a role in the export of functionally mature thymocytes.
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