Differentiation of regulatory Foxp3+ T cells in the thymic cortex

John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 0200, Australia.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2008; 105(33):11903-8. DOI: 10.1073/pnas.0801506105
Source: PubMed


Regulatory Foxp3(+) T cells (T(R)) are indispensable for preventing autoimmune pathology in multiple organs and tissues. During thymic differentiation T cell receptor (TCR)-ligand interactions within a certain increased affinity range, in conjunction with gammac-containing cytokine receptor signals, induce Foxp3 expression and thereby commit developing thymocytes to the T(R) lineage. The contribution of distinct MHC class II-expressing accessory cell types to the differentiation process of Foxp3(+) thymocytes remains controversial, because a unique role in this process has been ascribed to either thymic dendritic cells (tDC) or to medullary thymic epithelial cells (mTEC). Furthermore, it was suggested that the thymic medulla, where the bulk of the negative selection of self-reactive thymocytes takes place, provides a specialized microenvironment supporting T(R) differentiation. Here, we report that the cortex, as defined by cortical thymic epithelial cells (cTEC), is sufficient for supporting T(R) differentiation. MHC class II expression restricted to both cTEC and mTEC or to cTEC alone did not significantly affect the numbers of Foxp3(+) thymocytes. Furthermore, genetic or pharmacologic blockade of thymocyte migration resulted in a prominent accumulation of Foxp3(+) thymocytes in the cortex, demonstrating that secondary signals required for Foxp3 up-regulation exist in the cortex. Our results suggest that mTEC or tDC do not serve as a cell type singularly responsible for T(R) differentiation and that neither the cortex nor the medulla exclusively provides an environment suitable for Foxp3 induction. Instead, multiple accessory cell types probably contribute to the thymic generation of regulatory Foxp3(+) T cells.

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    • "These observations are consistent with a step-wise model (Burchill et al., 2008; Lio and Hsieh, 2008) in which Tregs are selected from late-stage, single-positive (CD4 + ) thymocytes (Fontenot et al., 2005a), whose TCRs engage high affinity ligands (Sakaguchi et al., 2008) presented by either medullary or cortical thymic epithelial cells (mTECs or cTECs) in the context of MHC class II (Aschenbrenner et al., 2007; Liston et al., 2008b) and in the presence of CD28 co-stimulation (Tai et al., 2005). Thus, TCR/CD28 engagement induces expression of CD25 by thymocytes , sensitizing them to IL-2, which instructs Foxp3 and CD25 expression in a Stat5-regulated manner (Burchill et al., 2008; Lio and Hsieh, 2008). "
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    ABSTRACT: Physiological health must balance immunological responsiveness against foreign pathogens with tolerance toward self-components and commensals. Disruption of this balance causes autoimmune diseases/chronic inflammation, in case of excessive immune responses, and persistent infection/immunodeficiency if regulatory components are overactive. This homeostasis occurs at two different levels: at a resting state to prevent autoimmune disease, as autoreactive effector T-cells (Teffs) are only partially deleted in the thymus, and during inflammation to prevent excessive tissue injury, contract the immune response, and enable tissue repair. Adaptive immune cells with regulatory function ("regulatory T-cells") are essential to control Teffs. Two sets of regulatory T cell are required to achieve the desired control: those emerging de novo from embryonic/neonatal thymus ("thymic" or tTregs), whose function is to control autoreactive Teffs to prevent autoimmune diseases, and those induced in the periphery ("peripheral" or pTregs) to acquire regulatory phenotype in response to pathogens/inflammation. The differentiation mechanisms of these cells determine their commitment to lineage and plasticity toward other phenotypes. tTregs, expressing high levels of IL-2 receptor alpha chain (CD25), and the transcription factor Foxp3, are the most important, since mutations or deletions in these genes cause fatal autoimmune diseases in both mice and men. In the periphery, instead, Foxp3(+) pTregs can be induced from naïve precursors in response to environmental signals. Here, we discuss molecular signatures and induction processes, mechanisms and sites of action, lineage stability, and differentiating characteristics of both Foxp3(+) and Foxp3(-) populations of regulatory T cells, derived from the thymus or induced peripherally. We relate these predicates to programs of cell-based therapy for the treatment of autoimmune diseases and induction of tolerance to transplants.
    Full-text · Article · Jun 2013 · Frontiers in Immunology
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    • "In the thymus, analysis at the single-cell level provided evidence for the induction of Foxp3 expression at the CD4+CD8+ double-positive (DP) stage [6], [7], [8], [9] and a precursor-progeny relationship between DP and CD4+CD8? single-positive (CD4SP) Foxp3+ thymocytes [8]. The prevailing view that thymic induction of Foxp3 expression occurs predominantly, if not exclusively, at the DP stage has been challenged by several observations, including the capacity of TCR transgenic thymocytes to initiate Antigen (Ag)-driven Foxp3+ Treg cell induction at the CD4SP stage [10] and the enrichment of precommitted immediate precursors to Foxp3+ Treg cells among CD25+Foxp3? "
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    ABSTRACT: CD4(+)CD25(+) regulatory T (Treg) cell lineage commitment and expression of the transcription factor Foxp3 can be induced at the CD4(+)CD8(+) double-positive (DP) and CD4(+)CD8(?) single-positive stages of thymic development, as well as in postthymic CD4(+) T cells in peripheral lymphoid tissues. The availability of transgenic mice with Foxp3-dependent fluorochrome reporter gene expression has greatly facilitated studies on the intra- and extrathymic generation of murine Foxp3(+) Treg cells. Here, we performed a comparative analysis of thymic Treg cell development and peripheral compartments of mature Treg cells in various transgenic strains with gene targeted and bacterial artificial chromosome (BAC)-driven Foxp3-fluorochrome expression. These studies revealed a relative deficiency of Foxp3(+) DP thymocytes selectively in mice with targeted insertion of the fluorochrome reporter gene coding sequence into the endogenous Foxp3 gene. While Foxp3 BAC-driven fluorochrome expression in ex vivo CD4(+) T cells was found to faithfully reflect Foxp3 protein expression, we provide evidence that Foxp3 BAC transgenesis can result in sizable populations of Foxp3(+) Treg cells that lack fluorochrome reporter expression. This could be attributed to both timely delayed up-regulation of BAC expression in developing Treg cells and the accumulation of peripheral Foxp3(+) Treg cells with continuous transcriptional inactivity of the Foxp3 BAC transgene.
    Full-text · Article · Aug 2012 · PLoS ONE
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    • "The CD4+CD25+FOXP3+ regulatory T (Treg) cells are required for proper maintenance of immunological self-tolerance and immune homeostasis [1]. Treg cells develop in the thymus as an independent CD4+ T cell lineage [2]–[4]. It is believed that epigenetic modifications serve as an important regulatory mechanism that mediates cell fate choice between the conventional T (Tconv) cells and Tregs, but there is a paucity of information related to the epigenetic changes that occur during Treg differentiation. "
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    ABSTRACT: Regulatory T cells (Treg) contribute to the crucial immunological processes of self-tolerance and immune homeostasis. Genomic mechanisms that regulate cell fate decisions leading to Treg or conventional T cells (Tconv) lineages and those underlying Treg function remain to be fully elucidated, especially at the histone modification level. We generated high-resolution genome-wide distribution maps of monomethylated histone H3 lysine 4 (H3K4me1) and trimethylated H3K4 (H3K4me3) in human CD4(+)CD25(+)FOXP3(+) Tregs and CD4(+)CD25(+)FOXP3(-) activated (a)Tconv cells by DNA sequencing-by-synthesis. 2115 H3K4me3 regions corresponded to proximal promoters; in Tregs, the genes associated with these regions included the master regulator FOXP3 and the chemokine (C-C motif) receptor 7 (CCR7). 41024 Treg-specific H3K4me1 regions were identified. The majority of the H3K4me1 regions differing between Treg and aTconv cells were located at promoter-distal sites, and in vitro reporter gene assays were used to evaluate and identify novel enhancer activity. We provide for the first time a comprehensive genome-wide dataset of lineage-specific H3K4me1 and H3K4me3 patterns in Treg and aTconv cells, which may control cell type-specific gene regulation. This basic principle is likely not restricted to the two closely-related T cell populations, but may apply generally to somatic cell lineages in adult organisms.
    Full-text · Article · Nov 2011 · PLoS ONE
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