Foxn1-β5t transcriptional axis controls CD8+ T-cell production in the thymus

Uddin, Muhammad Myn; Ohigashi, Izumi; Motosugi, Ryo; Nakayama, Tomomi; Sakata, Masayo; Hamazaki, Jun; Nishito, Yasumasa; Rodé, I; Tanaka, Keiji; Takemoto, Tadashi; Murata, Shigeo; Takahama, Yousuke

doi:10.1038/ncomms14419

Cited by 43 publications

(36 citation statements)

References 38 publications

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“…This strategy for TEC ablation was successfully used in our previous studies 8 , 20 , where conditional cell ablation was achieved by provision of the prodrug CB1954, which is converted into a cytotoxic agent by NTR 37 , 38 . The Psmb11 promoter fragment contains recognition sites for the Foxn1 transcription factor that are required for the expression of the Psmb11 gene 39 ; whether or not the Prss16 gene is also under the control of Foxn1 is not known. At E14.5 and later stages of embryonic development, expression of the Psmb11 : CFP-NTR transgene largely overlapped with expression of endogenous Psmb11 protein, as revealed by an anti-Psmb11 antibody; this finding suggests that the promoter fragment used here recapitulates the activity of endogenous regulatory elements of the Psmb11 gene (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Fundamental parameters of the developing thymic epithelium in the mouse

Hirakawa

Nagakubo

Kanzler

et al. 2018

Sci Rep

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The numbers of thymic epithelial cells (TECs) and thymocytes steadily increase during embryogenesis. To examine this dynamic, we generated several TEC-specific transgenic mouse lines, which express fluorescent proteins in the nucleus, the cytosol and in the membranes under the control of the Foxn1 promoter. These tools enabled us to determine TEC numbers in tissue sections by confocal fluorescent microscopy, and in the intact organ by light-sheet microscopy. Compared to histological procedures, flow cytometric analysis of thymic cellularity is shown to underestimate the numbers of TECs by one order of magnitude; using enzymatic digestion of thymic tissue, the loss of cortical TECs (cTECs) is several fold greater than that of medullary TECs (mTECs), although different cTEC subsets appear to be still present in the final preparation. Novel reporter lines driven by Psmb11 and Prss16 promoters revealed the trajectory of differentiation of cTEC-like cells, and, owing to the additional facility of conditional cell ablation, allowed us to follow the recovery of such cells after their depletion during embryogenesis. Multiparametric histological analyses indicate that the new transgenic reporter lines not only reveal the unique morphologies of different TEC subsets, but are also conducive to the analysis of the complex cellular interactions in the thymus.

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Section: Resultsmentioning

confidence: 99%

Fundamental parameters of the developing thymic epithelium in the mouse

Hirakawa

Nagakubo

Kanzler

et al. 2018

Sci Rep

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“…The transcription of b5t is regulated by Foxn1, a transcription factor that is essential for thymus organogenesis and hair follicle development (Uddin et al, 2017). Aberrant expression of b5t in the periphery has not been demonstrated to date.…”

Section: Discussionmentioning

confidence: 99%

Restricted Expression of the Thymoproteasome Is Required for Thymic Selection and Peripheral Homeostasis of CD8+ T Cells

et al. 2019

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The thymoproteasome subunit b5t is specifically expressed in cortical thymic epithelial cells (TECs) and generates unique peptides to support positive selection. In this study, using a mouse model ubiquitously expressing b5t, we showed that aberrant expression of self-peptides generated by b5t affects CD8 + T cell homeostasis, including thymic selection and maintenance of the peripheral naive pool of CD8 + T cells. In mice in which b5t was expressed both in cortical and medullary TECs, the abundance of CD8 + lineage thymocytes was reduced, and extra-thymic expression of b5t caused accumulation of CD8 + T cells with the memory or exhausted phenotype and induced autoreactive T cell responses. We found that thymoproteasomes are essential for positive selection but that the subsequent change in peptide repertoire in the medulla is also crucial for thymic selection and that b5t-derived peptide must be confined to the thymus to avoid autoimmunity in peripheral tissues.

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“…Many FOXN1 targets in cTECs regulate various steps of thymopoiesis: (i) regulation of lymphoid precursors migration in the thymus (Ccl25 and Cxcl12), (ii) DN thymocyte survival and proliferation (Ccl25, Cxcl12) and differentiation (Dll4, Cxcl12), and (iii) cortico-medullary thymocyte migration (Psmb11) (9,13,33,(38)(39)(40)(41)(42)(43)(44). In cTECs, FOXN1 targets also include genes involved in antigenic presentation essential for positive selection, such as cTEC-specific proteases (Psmb11, Prss16, and Ctsl) and stimulatory molecules important in TCR signaling (MHC-II, Cd83) (45)(46)(47)(48)(49)(50). During pregnancy and postpartum regeneration, all these genes followed a pattern of expression similar to that of Foxn1: (i) downregulation during pregnancy-induced involution; (ii) upregulation in early regeneration; and (iii) downregulation again in late regeneration (Figure 3A and Supplementary Table 2).…”

Section: The Pivotal Role Of Ctecs In Postpartum Thymic Regenerationmentioning

confidence: 99%

Qualitative Changes in Cortical Thymic Epithelial Cells Drive Postpartum Thymic Regeneration

et al. 2020

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During gestation, sex hormones cause a significant thymic involution which enhances fertility. This thymic involution is rapidly corrected following parturition. As thymic epithelial cells (TECs) are responsible for the regulation of thymopoiesis, we analyzed the sequential phenotypic and transcriptomic changes in TECs during the postpartum period in order to identify mechanisms triggering postpartum thymic regeneration. In particular, we performed flow cytometry analyses and deep RNA-sequencing on purified TEC subsets at several time points before and after parturition. We report that pregnancy-induced involution is not caused by loss of TECs since their number does not change during or after pregnancy. However, during pregnancy, we observed a significant depletion of all thymocyte subsets downstream of the double-negative 1 (DN1) differentiation stage. Variations in thymocyte numbers correlated with conspicuous changes in the transcriptome of cortical TECs (cTECs). The transcriptomic changes affected predominantly cTEC expression of Foxn1, its targets and several genes that are essential for thymopoiesis. By contrast, medullary TECs (mTECs) showed very little transcriptomic changes in the early postpartum regenerative phase, but seemed to respond to the expansion of single-positive (SP) thymocytes in the late phase of regeneration. Together, these results show that postpartum thymic regeneration is orchestrated by variations in expression of a well-defined subset of cTEC genes, that occur very early after parturition.

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Foxn1-β5t transcriptional axis controls CD8+ T-cell production in the thymus

Cited by 43 publications

References 38 publications

Fundamental parameters of the developing thymic epithelium in the mouse

Fundamental parameters of the developing thymic epithelium in the mouse

Restricted Expression of the Thymoproteasome Is Required for Thymic Selection and Peripheral Homeostasis of CD8+ T Cells

Qualitative Changes in Cortical Thymic Epithelial Cells Drive Postpartum Thymic Regeneration

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