Abstract
BackgroundThymic epithelial cell (TEC) microenvironments are essential for the recruitment of T cell precursors from the bone marrow, as well as the subsequent expansion and selection of thymocytes resulting in a mature self-tolerant T cell repertoire. The molecular mechanisms, which control both the initial development and subsequent maintenance of these critical microenvironments, are poorly defined. Wnt signaling has been shown to be important to the development of several epithelial tissues and organs. Regulation of Wnt signaling has also been shown to impact both early thymocyte and thymic epithelial development. However, early blocks in thymic organogenesis or death of the mice have prevented analysis of a role of canonical Wnt signaling in the maintenance of TECs in the postnatal thymus.Methodology/Principal FindingsHere we demonstrate that tetracycline-regulated expression of the canonical Wnt inhibitor DKK1 in TECs localized in both the cortex and medulla of adult mice, results in rapid thymic degeneration characterized by a loss of ΔNP63+ Foxn1+ and Aire+ TECs, loss of K5K8DP TECs thought to represent or contain an immature TEC progenitor, decreased TEC proliferation and the development of cystic structures, similar to an aged thymus. Removal of DKK1 from DKK1-involuted mice results in full recovery, suggesting that canonical Wnt signaling is required for the differentiation or proliferation of TEC populations needed for maintenance of properly organized adult thymic epithelial microenvironments.Conclusions/SignificanceTaken together, the results of this study demonstrate that canonical Wnt signaling within TECs is required for the maintenance of epithelial microenvironments in the postnatal thymus, possibly through effects on TEC progenitor/stem cell populations. Downstream targets of Wnt signaling, which are responsible for maintenance of these TEC progenitors may provide useful targets for therapies aimed at counteracting age associated thymic involution or the premature thymic degeneration associated with cancer therapy and bone marrow transplants.
Highlights
The thymus serves two functions essential for a properly functioning adaptive immune response
Several previous studies have demonstrated a role for canonical Wnt signaling in regulating early T cell development [46,54], as well as the development of the thymic epithelium [38,39,47,49] due to early death of the mice or early blocks in thymic development, analysis of a role for Wnt signaling in the maintenance of adult Thymic epithelial cell (TEC) microenvironments was not possible
We hypothesized that the resulting double transgenic tetODkk1;K5 promoterdriven tet inducer-VP16 transgene (K5rtTA) mice would produce high levels of DKK1 in the K5-expressing TEC subsets in response to the Dox, including the dominant K5+ Medullary thymic epithelial cells (mTECs) subset and the K5K8DP cTECs
Summary
The thymus serves two functions essential for a properly functioning adaptive immune response These are the generation of new T cells from hematopoietic stem cells (HSC) and the selection of T cells expressing a functional self-tolerant T cell receptor (TCR) repertoire. MTECs express a wide array of tissue restricted antigens (TRAs), so called ‘‘promiscuous gene expression’’ [15,16,17], some of which appear to be under the control of the AIRE transcription factor [18] These TRAs represent a pool of self-antigens, which are used to negatively select auto-reactive thymocytes to induce self-tolerance or differentiation of regulatory T cell subsets. Early blocks in thymic organogenesis or death of the mice have prevented analysis of a role of canonical Wnt signaling in the maintenance of TECs in the postnatal thymus
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