Guiding the action of the immune system: Interactions between the immune system and non-immune tissues (original) (raw)
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Nature Immunology, 2016
Thymic epithelial cell differentiation, growth and function depend on the expression of the transcription factor Foxn1, however its target genes have never been physically identified. Using novel static and inducible genetic model systems and chromatin studies, we provide now a genome wide map of direct Foxn1 target genes for postnatal thymic epithelia and define the Foxn1 binding motif. We detail the function of Foxn1 in these cells and demonstrate that in addition to the transcriptional control of genes involved in the attraction and lineage commitment of T cell precursors, Foxn1 regulates the expression of genes involved in antigen processing and thymocyte selection. Thus, critical events in thymic lympho-stromal cross-talk and T cell selection are indispensably choreographed by Foxn1. The thymic microenvironment is unique in its ability to promote the development and selection of naïve T cells with a repertoire purged of vital "self" specificities but prepared to react to injurious "non-self". Thymic epithelial cells (TEC), which can be categorized into separate cortical (cTEC) and medullary (mTEC) lineages1,2, are essential for this Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
A domain of Foxn1 required for crosstalk-dependent thymic epithelial cell differentiation
Nature Immunology, 2003
Thymic epithelial cells (TECs) are required for T cell maturation within the thymus. In the nude (Foxn1(nu/nu)) mouse, TECs fail to differentiate. We have generated a hypomorphic allele called Foxn1(Delta), from which an N-terminal domain was deleted. The phenotype was thymus specific, identifying a tissue-specific activity for this domain. Foxn1(Delta/Delta) mice showed abnormal thymic architecture, lacking cortical and medullary domains. In contrast to thymi in mice with the null allele, the Foxn1(Delta/Delta) thymus promoted T cell development, but with specific defects at both the double-negative and double-positive stages. Thus, initiation and progression of TEC differentiation are genetically separable functions of Foxn1, and the N-terminal domain is required for crosstalk-dependent TEC differentiation.
Early events in the thymus affect the balance of effector and regulatory T cells
Nature, 2006
In cellular immunology the critical balance between effector and regulatory mechanisms is highlighted by serious immunopathologies attributable to mutations in Foxp3, a transcription factor required for a major subset of regulatory T (T R ) cells 1-3 . Thus, many studies have focused on the developmental origin of T R cells, with the prevailing view that they emerge in the thymus from latestage T-cell progenitors whose T-cell receptors (TCRs) engage high affinity (agonist) ligands 4-6 . This study questions the completeness of that interpretation. Here we show that without any obvious effect on TCR-mediated selection, the normal differentiation of mouse cd T cells into potent cytolytic and interferon-csecreting effector cells is switched towards an aggregate regulatory phenotype by limiting the capacity of CD4 1 CD8 1 T-cell progenitors to influence in trans early cd cell progenitors. Unexpectedly, we found that the propensity of early TCR-ab 1 progenitors to differentiate into Foxp3 1 T R cells is also regulated in trans by CD4 1 CD8 1 T-cell progenitor cells, before agonist selection.
Stepwise development of thymic microenvironments in vivo is regulated by thymocyte subsets
Development (Cambridge, England), 2000
T-cell development is under the tight control of thymic microenvironments. Conversely, the integrity of thymic microenvironments depends on the physical presence of developing thymocytes, a phenomenon designated as 'thymic crosstalk'. We now show, using three types of immunodeficient mice, i.e. CD3(epsilon) transgenic mice, RAG(null) mice and RAG(null)-bone-marrow-transplanted CD3(epsilon) transgenic mice, that the control point in lymphoid development where triple negative (CD3(-),CD4(-),CD8(-)) thymocytes progress from CD44(+)CD25(-) towards CD44(-)CD25(+), influences the development of epithelial cells, critically inducing the extra, third dimension in the organization of the epithelial cells in the cortex. This tertiary configuration of the thymic epithelium is a typical feature for the thymus, enabling lymphostromal interaction during T-cell development. Crosstalk signals at this control point also induce the formation of thymic nurse cells. Moreover, our data indicate ...