Thymopoiesis in mice depends on a
            <i>Foxn1</i>
            -positive thymic epithelial cell lineage

Corbeaux, Tatiana; Hess, Isabell; Swann, Jeremy B.; Kanzler, Benoı̂t; Haas-Assenbaum, Annette; Boehm, Thomas

doi:10.1073/pnas.1004623107

Cited by 115 publications

(141 citation statements)

References 30 publications

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“…The early "ubiquitous" expression of Foxn1 in the developing thymus is in line with the reported fate-mapping data (37,38). We addressed the origin of the few Foxn1 2 TECs in embryonic mice.…”

Section: Discussionsupporting

confidence: 60%

Foxn1 Protein Expression in the Developing, Aging, and Regenerating Thymus

Rodé

Martins

Küblbeck

et al. 2015

The Journal of Immunology

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The forkhead box N1 (Foxn1) protein is the key regulator of thymic epithelial cell (TEC) development, yet how Foxn1 functions remains largely unknown. All mature TECs arise from Foxn1-expressing progenitors/immature TECs and it is widely assumed that TECs as a whole are defined by Foxn1 expression. However, data on the Foxn1 protein are virtually lacking. In this study, we developed novel tools to visualize Foxn1 protein expression at single-cell resolution. We generated Foxn1 knock-in mice expressing a C-terminal hemagglutinin-tagged Foxn1 protein, and a cytometry-grade monoclonal anti-Foxn1 Ab. We evaluated Foxn1 expression patterns in TEC subsets and its dynamics during normal thymus development, aging, injury, and regeneration. Upon challenges, upregulation of Foxn1 was a common feature of thymus regeneration, but the timing of Foxn1 expression changed and the responding TEC subsets depended on the type of treatment. Whereas dexamethasone and recombinant human fibroblast growth factor 7 promoted expansion of Foxn1+Ly51+CD80− TECs, castration led to expansion of Foxn1+Ly51−CD80+ TECs. Collectively, Foxn1 expression is highly heterogeneous in the normal thymus, with large fractions of Foxn1low or Foxn1− TECs accumulating with age. Furthermore, Foxn1 expression is responsive to perturbations.

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Section: Discussionsupporting

confidence: 60%

Foxn1 Protein Expression in the Developing, Aging, and Regenerating Thymus

Rodé

Martins

Küblbeck

et al. 2015

The Journal of Immunology

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“…42,43,48 Our results clearly indicate that Wnt4 regulates the number of TECs in the thymus and consequently the number of intrathymic niches available for thymus-seeding progenitors ( Figures 4A, 5A, and 6). Conversely, Wnt4 also is capable of directly influencing the expansion of the most immature cKit hi thymocytes in vitro ( Figure 3C-D).…”

Section: Discussionmentioning

confidence: 60%

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

Heinonen

Vanegas

Brochu

et al. 2011

Blood

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Thymus atrophy is the most common immunopathology in humans, and its occurrence is hastened by several factors that coalesce in patients receiving chemotherapy and most of all in recipients of hematopoietic cell transplantation. We have shown previously that posthematopoietic cell transplantation thymic function was improved by retroviral overexpression of Wnt4 in donor hematopoietic cells. Here, by using both conventional and conditional null mutant mice, we show that Wnt4 regulates steady-state thymic cellularity by a thymic epithelial cell (TEC)-dependent mechanism. The absence of Wnt4 suppressed fetal and postnatal thymic expansion and resulted in decreased TEC numbers, an alteration of the medullary-to-cortical TEC ratio, and a disproportionate loss of the most immature cKit hi thymocyte precursors. Wnt4 also is implicated in the maintenance of adult thymopoiesis, although the impact of its deletion once thymic involution has been initiated is more subtle. Together, our results show that Wnt4 controls thymic size by modulating TEC expansion and the earliest, TEC-dependent steps of thymocyte development both in the fetal and postnatal thymus. Wnt4 and its downstream signaling pathways could thus represent interesting candidates to improve thymic output in subjects with thymic atrophy. (Blood. 2011;118(19): 5163-5173)

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“…Several investigators have also shown that, in addition to maintain existing TECs, FOXN1 also regulates TEC progenitors [15,16,18,27,31], which may also contribute to the increased number of TECs. The number of ETPs was also significantly increased after rFOXN1 treatment.…”

Section: Discussionmentioning

confidence: 99%

“…FOXN1 is required not only for TEC development in fetal thymus, but also for maintenance of the postnatal thymus [15,16,23,24,26]. The reduced expression or induced deletion of FOXN1 resulted in reduced TEC number and a disrupted thymic microenvironment [16,18,22,24,27]. Conversely, an intrathymic injection of FOXN1 cDNA-bearing plasmid into the thymus of aged mice or FOXN1 transgenic mice resulted in an increased number of TECs, leading to enhanced thymopoiesis and an increased naïve T-cell output [23,25].…”

Section: Introductionmentioning

confidence: 99%

“…These results suggest that FOXN1 induced mTEC proliferation is due, at least in part, to the enhanced expression of cyclin D1. Whether cyclin D1 and p53 are the directly or indirectly downstream target genes remains to be determined.In addition to an increased number of mature TECs, rFOXN1 treatment also increased the number of MHC II lo immature TECs.Several investigators have also shown that, in addition to maintain existing TECs, FOXN1 also regulates TEC progenitors [15,16,18,27,31], which may also contribute to the increased number of TECs. The number of ETPs was also significantly increased after rFOXN1 treatment.…”

mentioning

confidence: 99%

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FOXN1 recombinant protein enhances T‐cell regeneration after hematopoietic stem cell transplantation in mice

Song

Zhu

et al. 2016

Eur J Immunol

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A prolonged period of T-cell recovery is the major challenge in hematopoietic stem cell transplantation (HSCT). Thymic epithelial cells (TECs) are the major component of the thymic microenvironment for T-cell generation. However, TECs undergo degeneration over time. FOXN1 plays a critical role in TEC development and is required to maintain adult TECs for thymopoiesis. To investigate the potential application of FOXN1, we have cloned and expressed recombinant FOXN1 protein (rFOXN1) that was fused with cellpenetrating peptides. We show here that the rFOXN1 protein can translocate from the cell surface into the cytoplasm and nucleus. Administration of rFOXN1 into both congenic and allogeneic HSCT recipient mice increased the number of TECs, resulting in enhanced thymopoiesis that led to an increased number of functional T cells in the periphery. The increased number of TECs is due to the enhanced survival and proliferation of TECs. Our results suggest that rFOXN1 has the potential to be used in enhancing T-cell regeneration in patients following HSCT.Keywords: FOXN1 r Hematopoietic stem cell transplantation r T-cell generation r Thymic epithelial cells r Thymus Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionHSCT is widely used in the treatment of hematopoietic and nonhematopoietic diseases. However, this procedure often suffers from a long period of T-cell recovery, which contributes to increased incidences of infection and relapses of cancer [1][2][3][4][5][6]. Therefore, strategies to enhance T-cell regeneration after HSCT would be greatly beneficial.Correspondence: Dr. Laijun Lai e-mail: laijun.lai@uconn.edu T-cell development occurs primarily in the thymus, and is critically dependent on the thymic microenvironment, in which TECs are the major component. The importance of TECs in thymocyte development has been highlighted by the fact that abnormal TEC development results in immunodeficiency and autoimmunity [7,8]. It is known that TECs undergo a qualitative and quantitative loss over time [8][9][10]. In addition, radiation, chemotherapy, immunosuppressive drugs, and infections, etc. may injure the TECs. Therefore, strategies to restore TECs should lead to enhanced T-cell regeneration and adaptive immunity.FOXN1 is a member of the winged helix/forkhead box transcription factor family. It is generally acknowledged that FOXN1 is a pivotal regulator for TEC development [11][12][13][14][15][16][17][18][19]. Mice homozygous for loss-of-function mutation in FOXN1 display the 'nude' phenotype (FOXN1 nu/nu ), which is characterized by congenital athymia and hairlessness. A mutation in the human FOXN1 gene also results in a nude phenotype [20,21]. FOXN1 is expressed in fetal thymus and postnatal TECs and its expression is progressively down-regulated with aging [15,16,[22][23][24][25]. FOXN1 is required not only for TEC development in fetal thymus, but also for maintenance of the postnatal thymus [15,16,23,24,26]. The reduced expression or indu...

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Thymopoiesis in mice depends on a Foxn1 -positive thymic epithelial cell lineage

Cited by 115 publications

References 30 publications

Foxn1 Protein Expression in the Developing, Aging, and Regenerating Thymus

Foxn1 Protein Expression in the Developing, Aging, and Regenerating Thymus

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

FOXN1 recombinant protein enhances T‐cell regeneration after hematopoietic stem cell transplantation in mice

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