Stabilized β-Catenin in Thymic Epithelial Cells Blocks Thymus Development and Function

IL-7 is a cytokine essential for T cell development and survival. However, the local function of IL-7 produced by thymic epithelial cells (TECs) is poorly understood. To address this question, we generated IL-7–floxed mice and crossed them with FoxN1 promoter–driven Cre (FoxN1-Cre) mice to establish knockout mice conditionally deficient for the expression of IL-7 by TECs. We found that αβ and γδ T cells were significantly reduced in the thymus of IL-7f/f FoxN1-Cre mice. Proportion of mature single-positive thymocytes was increased. In lymph nodes and the spleen, the numbers of T cells were partially restored in IL-7f/f FoxN1-Cre mice. In addition, γδ T cells were absent from the fetal thymus and epidermis of IL-7f/f FoxN1-Cre mice. Furthermore, TCRγδ+ intraepithelial lymphocytes (IELs) were significantly decreased in the small intestines of IL-7f/f FoxN1-Cre mice. To evaluate the function of IL-7 produced in the intestine, we crossed the IL-7f/f mice with villin promoter–driven Cre (Vil-Cre) mice to obtain the mice deficient in IL-7 production from intestinal epithelial cells. We observed that αβ and γδ IELs of IL-7f/f Vil-Cre mice were comparable to control mice. Collectively, our results suggest that TEC-derived IL-7 plays a major role in proliferation, survival, and maturation of thymocytes and is indispensable for γδ T cell development. This study also demonstrates that IL-7 produced in the thymus is essential for the development of γδ IELs and indicates the thymic origin of γδ IELs.

show abstract

“…Mice IL-7-floxed and FoxN1-Cre Tg mice were reported previously (26,27). Vil-Cre Tg mice were obtained from The Jackson Laboratory (28).…”

Section: Methodsmentioning

confidence: 99%

IL-7 Produced by Thymic Epithelial Cells Plays a Major Role in the Development of Thymocytes and TCRγδ+ Intraepithelial Lymphocytes

Shitara

Hara

Liang

et al. 2013

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Furthermore, the thymic stroma was demonstrated to be Wnt receptive (15,17,29). Gpr177 is a Wntspecific cargo receptor that is required to transport Wnt ligands to the cell surface and, thus, for Wnt secretion (22,23).…”

Section: Loss Of Wnt Secretion By Tecs Impairs Thymus Developmentmentioning

confidence: 99%

Thymic Epithelial Cells Are a Nonredundant Source of Wnt Ligands for Thymus Development

Brunk

Augustin

Meister

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Wnt signaling has been implicated in T cell development. However, it remained unclear which cell type is the major source of Wnt ligands and to what extent thymic epithelial cell (TEC) development is dependent on Wnt signaling. In this study, we analyzed the role of Wnt ligands provided by TECs for the development of T cells and TECs without manipulating the intracellular Wnt signaling machinery in either cell type. To this end, we used conditional knockout mice (FoxN1-Gpr177) in which TECs are unable to secrete Wnt ligands. Gpr177 (Evi/Wls) is a Wnt-specific cargo receptor that is required for the secretion of Wnt ligands. We found that TECs are the main source of Wnt ligands in the thymus, which serves a nonredundant role, and lack of TEC-provided Wnt ligands led to thymic hypotrophy, as well as a reduced peripheral T cell pool. Despite being reduced in numbers, T cells that developed in the absence of TEC-secreted Wnt ligands were functionally competent, and the subset composition of the peripheral T cell pool was not affected. Thus, our data suggest that T cell development is not directly dependent on TEC-provided Wnt ligands. Rather, TEC-secreted Wnt ligands are essential for normal thymus development and normal peripheral T cell frequencies but are dispensable for T cell function in the periphery.

show abstract

“…14 Conversely, the Wnt antagonist Kremen was shown to be necessary for the establishment of normal TEC numbers during thymic organogenesis. 19 Interestingly, stabilization of ␤-catenin in epithelial cells prevented thymic development, 20,21 despite the fact that canonical Wnt signaling, and in particular Wnt4, have been suggested to induce FoxN1 expression. 22 However, none of these studies have focused on the effect of an individual Wnt family protein nor have they considered the potential impact of noncanonical Wnt signaling.…”

Section: Introductionmentioning

confidence: 99%

Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors

Heinonen

Vanegas

Brochu

et al. 2011

Blood

View full text Add to dashboard Cite

Thymus atrophy is the most common immunopathology in humans, and its occurrence is hastened by several factors that coalesce in patients receiving chemotherapy and most of all in recipients of hematopoietic cell transplantation. We have shown previously that posthematopoietic cell transplantation thymic function was improved by retroviral overexpression of Wnt4 in donor hematopoietic cells. Here, by using both conventional and conditional null mutant mice, we show that Wnt4 regulates steady-state thymic cellularity by a thymic epithelial cell (TEC)-dependent mechanism. The absence of Wnt4 suppressed fetal and postnatal thymic expansion and resulted in decreased TEC numbers, an alteration of the medullary-to-cortical TEC ratio, and a disproportionate loss of the most immature cKit hi thymocyte precursors. Wnt4 also is implicated in the maintenance of adult thymopoiesis, although the impact of its deletion once thymic involution has been initiated is more subtle. Together, our results show that Wnt4 controls thymic size by modulating TEC expansion and the earliest, TEC-dependent steps of thymocyte development both in the fetal and postnatal thymus. Wnt4 and its downstream signaling pathways could thus represent interesting candidates to improve thymic output in subjects with thymic atrophy. (Blood. 2011;118(19): 5163-5173)

show abstract

Stabilized β-Catenin in Thymic Epithelial Cells Blocks Thymus Development and Function

Cited by 74 publications

References 64 publications

IL-7 Produced by Thymic Epithelial Cells Plays a Major Role in the Development of Thymocytes and TCRγδ+ Intraepithelial Lymphocytes

IL-7 Produced by Thymic Epithelial Cells Plays a Major Role in the Development of Thymocytes and TCRγδ+ Intraepithelial Lymphocytes

Thymic Epithelial Cells Are a Nonredundant Source of Wnt Ligands for Thymus Development

Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors

Contact Info

Product

Resources

About