Molecular Insights Into the Causes of Human Thymic Hypoplasia With Animal Models

Abstract

22q11.2 deletion syndrome (DiGeorge), CHARGE syndrome, Nude/SCID and otofaciocervical syndrome type 2 (OTFCS2) are distinct clinical conditions in humans that can result in hypoplasia and occasionally, aplasia of the thymus. Thymic hypoplasia/aplasia is first suggested by absence or significantly reduced numbers of recent thymic emigrants, revealed in standard-of-care newborn screens for T cell receptor excision circles (TRECs). Subsequent clinical assessments will often indicate whether genetic mutations are causal to the low T cell output from the thymus. However, the molecular mechanisms leading to the thymic hypoplasia/aplasia in diverse human syndromes are not fully understood, partly because the problems of the thymus originate during embryogenesis. Rodent and Zebrafish models of these clinical syndromes have been used to better define the underlying basis of the clinical presentations. Results from these animal models are uncovering contributions of different cell types in the specification, differentiation, and expansion of the thymus. Cell populations such as epithelial cells, mesenchymal cells, endothelial cells, and thymocytes are variably affected depending on the human syndrome responsible for the thymic hypoplasia. In the current review, findings from the diverse animal models will be described in relation to the clinical phenotypes. Importantly, these results are suggesting new strategies for regenerating thymic tissue in patients with distinct congenital disorders.

Keywords: 22q11.2 deletion syndrome; CHD7; FOXN1; PAX1; TECs; mesenchymal cells; thymic hypoplasia; thymus development.

Figure 1

The specification and expansion of the thymus during embryogenesis in normal and disease states. (A) Cartoon diagram illustrating the development process of the thymus along with the various transcription factors and gene products required. The genes that have roles in the specification of the human pharyngeal apparatus that affects the 3rd pharyngeal pouch (thymus and parathyroid) are shown in brown, while those confirmed importance for these processes in mice are in blue. (B) Transverse tissue sections or intact thymic lobes were isolated from normal embryos at the indicated ages of gestation. The transverse sections or whole mounts of the tissue were prepared for immunohistochemistry and H&E staining. Antibodies against vascular smooth muscle, pdgfr-a (alpha) marking the mesenchymal cells and thymic capsule, pdgfr-b (beta) delineating mesenchymal cells and the vasculature, cytokeratin (TECs) and laminin were used, with the colors indicated below the image. (C) Thymocyte subset distributions present in e19–19.5 embryonic thymuses from control C57BL/6 mice, those modeling 22q11.2 deletion syndrome (Tbx1^neo2/neo2) and those with compound heterozygous mutations in Foxn1 (Foxn1^933/1089) are shown. The Foxn1 mutations genocopy that identified in a human patient (22). Both control and 22q11.2del thymuses have similar distributions of CD4 and CD8 thymocyte subset percentages, suggesting normal TEC functions. The Foxn1 mutant mice are blocked at the CD4⁻CD8⁻ subset, indicating a severe TEC dysfunction.