RESUMO
In the thymus, interactions between immature thymocytes and thymic epithelial cells (TECs) regulate the development and selection of self-tolerant MHC-restricted T cells. Despite the importance of cortical (cTEC) and medullary (mTEC) thymic epithelial cells in fostering T cell production, events in TEC development are still unclear. Although precursor-product relationships during mTEC development have been reported, and some genetic regulators of mTEC development have been identified, stages in cTEC development occurring downstream of recently identified bipotent cTEC/mTEC progenitors remain poorly defined. In this study, we combine analysis of differentiation, proliferation, and gene expression of TECs in the murine thymus, that has enabled us to identify cTEC progenitors, define multiple stages in cTEC development, and identify novel checkpoints in development of the cTEC lineage. We show an essential requirement for FoxN1 in the initial development of cTEC from bipotent progenitors, and demonstrate a stage-specific requirement for CD4(-)8(-) thymocytes in later stages of cTEC development. Collectively, our data establish a program of cTEC development that should provide insight into the formation and function of the thymic cortex for T cell development.
Assuntos
Diferenciação Celular/imunologia , Células Epiteliais/citologia , Células Epiteliais/imunologia , Timo/citologia , Timo/imunologia , Animais , Comunicação Celular/imunologia , Linhagem da Célula/imunologia , Proliferação de Células , Células Epiteliais/metabolismo , Antígenos de Histocompatibilidade Classe II/biossíntese , Antígenos de Histocompatibilidade Classe II/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Células Precursoras de Linfócitos T/citologia , Células Precursoras de Linfócitos T/imunologia , Células Precursoras de Linfócitos T/metabolismo , Transdução de Sinais/imunologia , Timo/embriologia , Timo/metabolismoRESUMO
In this study, we show that in the absence of a protective NK cell response, murine CMV causes destruction of splenic white and red pulp pulp areas in the first few days of infection. Destruction of T zone stroma is associated with almost complete loss of dendritic cells and T cells. We provide evidence that the virus replicates in red and white pulp stroma in vivo and in vitro. Control of white pulp viral replication is associated with migration of murine CMV-specific activated NK cells to white pulp areas, where they associate directly with podoplanin-expressing T zone stromal cells. Our data explain how NK cells protect the lymphoid-rich white pulp areas from CMV, allowing protective adaptive T cell-dependent immune responses to develop, and how this mechanism might break down in immunocompromised patients.