Crosstalk Control of Thymic Epithelial Development

描述（由申请人提供）：胸腺上皮细胞（TECs）负责调节未成熟胸腺细胞向功能自我耐受的成熟T细胞的发育。一种常见的内胚层来源的TEC祖细胞最近被证明可以产生皮层和髓质TEC亚群，然而，调节这一过程的信号通路和细胞间相互作用尚不清楚。TEC的发展和组织依赖于从发育中的胸腺细胞通过上皮网络迁移时接收到的串扰信号。本研究的目的是确定SP胸腺细胞/TEC相互作用的性质和功能，这些相互作用调节胸腺髓质的发育，胸腺微环境对中枢耐受至关重要。通过将成熟T细胞过继转移到T细胞发育阻滞的小鼠体内诱导髓质重建，将用于测试特异性T细胞/TEC相互作用的贡献。

DESCRIPTION (provided by applicant): The thymic epithelial cells (TECs) are responsible for regulating the development of immature thymocytes into functional self-tolerant mature T cells. A common endoderm-derived TEC progenitor was recently shown to give rise to both cortical and medullary TEC subsets, however, the signaling pathways and cell-to-cell interactions that regulate this process are poorly defined. TEC development and organization is dependent on crosstalk signals received from developing thymocytes as they migrate through the epithelial network. The goal of this study will be to define both the nature and function of the SP thymocyte/TEC interactions that regulate development of the thymic medulla, the thymic microenvironment that is critically responsible for central tolerance. The medullary reconstitution induced by adoptive transfer of mature T cells into mice with blocks in T cell development will be used to test the contribution of specific T cell/TEC interactions. We propose to: (1) use MHC class I / MHC class II double KO mice to determine if the expansion and differentiation of the thymic medulla is dependent on TCR/MHC interactions and identify the specific contributions of CD4 SP, CDS SP and Tregs, in this process; (2) use both fetal thymic organ cultures and medullary reconstitution assays in a newly developed Wnt signaling reporter mouse strain, to access the contribution of Wnt signaling in mTEC development and determine if soluble Wnt inhibitory molecules secreted by SP thymocytes inhibit the canonical Wnt signaling pathway in TECs, thereby providing a molecular switch that is necessary for mTEC development from precursor cells. Fully understanding the signaling pathways and cellular interactions which contribute to TEC development and organization will be critical to designing rational therapeutic strategies to counteract age-associated thymic involution and thymic architecture defects associated with autoimmunity. These strategies will also significantly impact the effectiveness of bone marrow transplantation for cancer treatment by counteracting the severe premature thymic degeneration associated with preparative cytoablative treatments including chemotherapy and radiation, as well as post-transplant GVHD.