Severe Defect in Thymic Development in an Insertional Mutant Mouse Model

Abstract

Transgenic mice were generated expressing NK1.1, an NK cell-associated receptor, under control of the human CD2 promoter. Unexpectedly, one of the founder lines, Tg66, showed a marked defect in thymic development characterized by disorganized architecture and small size. Mapping of the transgene insertion by fluorescence in situ hybridization revealed integration in chromosome 2, band G. Already from postnatal day 3, the thymic architecture was disturbed with a preferential loss of cortical thymic epithelial cells, a feature that became more pronounced over time. Compared with wild-type mice, total thymic cell numbers decreased dramatically between 10 and 20 days of age. Thymocytes isolated from adult Tg66 mice were predominantly immature double-negative cells, indicating a block in thymic development at an early stage of differentiation. Consequently, Tg66 mice had reduced numbers of peripheral CD4+ and CD8+ T cells. Bone marrow from Tg66 mice readily reconstituted thymi of irradiated wild-type as well as RAG-deficient mice. This indicates that the primary defect in Tg66 mice resided in nonhemopoietic stromal cells of the thymus. The phenotype is observed in mice heterozygous for the insertion and does not resemble any known mutations affecting thymic development. Preliminary studies in mice homozygous for transgene insertion reveal a more accelerated and pronounced phenotype suggesting a semidominant effect. The Tg66 mice may serve as a useful model to identify genes regulating thymic epithelial cell differentiation, thymic development, and function.

The thymic cortical epithelium determines the TCR repertoire of IL ‐17‐producing γδT cells

“…Furthermore, cTECs highly produce endosomal/lysosomal proteases, cathepsin L and thymus‐specific serine protease , which contribute to the generation of MHC class II‐bound peptides and positive selection of certain repertoire of CD4 T cells. However, when compared with mTECs, the physiological significance of cTECs has been less addressed, partly because of a few reports on cTEC‐deficient mice . Thus, whether and how cTECs contribute to the development and function of the immune system, other than in the context of positive selection of αβT cells, remains to be elucidated.…”

Jagged1 overexpression on T cells induces thymic regulatory T cells leading to thymic involution

“…Not surprisingly, loss of the thymus is related to a reduced number of T cells in the periphery (Fig. 1B, (18)). We found that the defect was associated with Jagged1 expression on T cells since we could find increased levels of Jag1 at the RNA level and significant increase in the surface expression of Jagged1 on T cells in the periphery and in the thymus (Fig.…”

“…C57Bl/6 (B6), tg66, tg71 (18) and C57Bl/6 perforin (B6. pfp ) −/− (19) mice were bred and housed under standard conditions at the Department Microbiology and Tumor and Cell Biology, Karolinska Institutet, Stockholm.…”

Thymic cytoarchitecture changes in mice exposed to vanadium

“…the cortex and the medulla, and each has different types of TEC (Blackburn & Manley 2004;Osada et al 2006). These cells create small-specialized microenvironments to differentiate immature T-cells (Assarsson et al 2007). Immature T-cells exit the bone marrow and enter into the thymus in the cortico-medullar region, where thereafter they can interact with TEC and DC to initiate a programed organized differentiation process.…”