Thymic epithelial cells provide Wnt signals to developing thymocytes

Abstract

Interactions with thymic stromal cells are known to be critical for the development of T cells from progenitors entering the thymus, yet the molecular mechanisms of stromal cell function remain poorly understood. Accumulating evidence has highlighted the importance of gcatenin-mediated activation of T cell factor (TCF)/lymphoid enhancer factor (LEF) transcription during thymocyte development. As regulation of this signaling pathway is controlled by binding of soluble Wnt proteins to cell surface Frizzled (Fz) receptors, we studied components of Wnt/Fz-mediated signaling in the context of stromal cell regulation of thymocyte development. We show that mRNA for a variety of Wnt family members, notably Wnt-4, Wnt7a and 7b, and Wnt-10a and 10b, are expressed by thymic epithelium rather then by thymocytes, while thymocytes demonstrate a developmentally regulated pattern of Fz receptor expression. Collectively these findings suggest (1) a functional role for Wnt-producing thymic epithelium in determining TCF/LEF-mediated transcriptional regulation in Fz-bearing thymocytes, and (2) a role for defined Wnt-Fz interactions at successive stages of thymocyte maturation. In support of this we show that separation of thymocytes from Wnt-producing epithelial cells and the thymic microenvironment, triggers g -catenin phosphorylation and degradation in thymocytes. Thus, sustained exposure to Wnt in the context of an intact stromal microenvironment is necessary for stabilization of g -catenin-mediated signaling in thymocytes.

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

“…Wnt4 has been shown previously to be expressed in fetal TECs, 22,33 but little is known on its potential expression by other thymic stromal components and thymocyte subsets. We now compared Wnt4 mRNA expression by qRT-PCR in different thymic stromal fractions (TECs, endothelial cells, and fibroblasts) as well as thymocytes both in E18.5 fetal thymus and in young adult mice.…”

Noncanonical Wnt signaling promotes apoptosis in thymocyte development

“…Numerous Wnt genes are expressed in thymocytes or in thymic epithelial stromal cells ( 22 ), and overexpression of Wnt genes can increase thymocyte proliferation in vitro ( 23 ). Mice defi cient in LEF1/TCF1 are depleted of ␣ ␤ lineage thymocytes, and overexpression of extracellular Wnt inhibitors can partially block ␣ ␤ T cell development in fetal thymic organ cultures (FTOCs) ( 24 -26 ), suggesting that canonical Wnt signaling is essential for normal thymocyte development.…”

Notch and Wnt signaling in T-lymphocyte development and acute lymphoblastic leukemia

“…[79][80][81][82] Conversely, Fz receptors are expressed primarily by the thymocytes, but also by stromal cells. 79 79 Recently, our group has shown that mainly DN1-3 thymocytes undergo Wnt signaling.…”

“…Presence of b-catenin mRNA was detected in all thymoycte subsets. 80 Mice with b-catenin deleted in all T cells from DN3 onwards showed impaired T-cell development at the b-selection checkpoint, 90 but mice transplanted with HSCs in which b-catenin had been inducibly deleted, did not show in any thymic defect. 91 As possible explanation, redundancy between b-catenin and its homologue plakoglobin (g-catenin) has been suggested.…”