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Physiologic Thymic Involution Underlies Age-Dependent Accumulation of Senescence-Associated CD4+ T cells / 生理的胸腺退縮は加齢に伴う老化関連CD4+T細胞増加の一因であるSato, Kyosuke 26 March 2018 (has links)
京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13160号 / 論医博第2147号 / 新制||医||1029(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 生田 宏一, 教授 杉田 昌彦, 教授 椛島 健治 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM
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Prevention and reversal of thymus involution mediated by the transcription factor Foxn1Bredenkamp, Nicholas January 2011 (has links)
Central to the age-associated decrease in immune system function, characterised by the increase in the frequency and severity of infections and autoimmune diseases, is the decrease in production of naïve T cells by the thymus. This results from the targeted degeneration or involution of the thymus with age. One of the principal causes of involution is the loss of organisation and functionality of the thymic epithelium, which confers the primary function of the organ via interactive regulation of T cell development. Although the mechanisms that govern the deterioration of the thymic epithelium are poorly understood, a number of recent reports indicate that the transcription factor, Foxn1, is required to maintain this compartment in the postnatal thymus. Thus, the first aim of this study was to precisely profile Foxn1 expression levels in aging postnatal thymic epithelial cells. The second aim was to investigate the effects of upregulating Foxn1 in the aging thymus, which was achieved using a novel, regulatable Foxn1 mouse model generated during this study. In this study I show that Foxn1 is expressed at different levels in different postnatal thymic epithelial cell (TEC) sub-populations suggesting a dosage-dependent mode of action for Foxn1. Additionally, using two experimental approaches, I show that Foxn1 expression decreases with age in TECs, supporting the current data that implicate the loss of Foxn1 as a potential cause of thymus involution. Next, I generated a tissue-specific, regulatable Foxn1 mouse model that allowed me to modulate Foxn1 expression in the postnatal thymus. Firstly, using this model, I show that thymus involution can be prevented by the up-regulation and maintenance of Foxn1 expression from the onset of involution. Thymi that up-regulated Foxn1 were overtly larger and exhibited greater cellularity in both the thymocyte and epithelial compartments compared to age matched controls. Additionally, the larger TEC compartment contained a higher proportion of functional and proliferating TECs that upregulated a panel of genes involved in TEC development and function. Next, I show that Foxn1 up-regulation in aged, involuted thymi is sufficient to partially reverse involution, as shown by an increase in TEC organisation and intrathymic T cell numbers. While other strategies that promote thymic rebound or reversal have been reported, including cytokine treatment or sex steroid ablation, these approaches are complicated by side effects and toxicity. Hence, I propose a novel model for immune reconstitution through the regulation of Foxn1 expression in the postnatal thymus.
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CXCR3high CD8+ T cells with naive phenotype and high capacity for IFN-γproduction are generated during homeostatic T-cell proliferation / IFN-γ産生能の高いCXCR3high ナイーブ型CD8陽性 T 細胞がT細胞の恒常性増殖により産生されるOgura(Kato), Aiko 25 March 2019 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21636号 / 医博第4442号 / 新制||医||1034(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 生田 宏一, 教授 杉田 昌彦, 教授 竹内 理 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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Découverte de cellules souches potentielles de l’épithélium thymiqueDumont-Lagacé, Maude 05 1900 (has links)
Le thymus subit un vieillissement précoce, appelé involution thymique, qui cause une perte de fonction du thymus avec l’âge. À ce jour, les mécanismes de renouvellement des cellules épithéliales thymiques (TECs) sont encore mal compris, c’est pourquoi nous avons voulu identifier les cellules souches de l’épithélium thymique. Comme les cellules souches sont quiescentes dans plusieurs tissus, les objectifs de notre étude étaient de déterminer si l’épithélium thymique contenait des cellules quiescentes et d’étudier la cinétique de prolifération des TECs chez les souris jeunes et adultes. Pour ce faire, nous avons utilisé une souris transgénique (H2B-GFP Tet-On) nous permettant d’identifier les cellules ne se divisant pas sur une longue période de temps (LRC, label-retaining cells¬). Nous avons d’abord montré que les TECs proliféraient plus rapidement chez les femelles que les mâles. De plus, nous avons trouvé plusieurs différences entre l’épithélium thymique post-natal et adulte : (1) les TECs corticales (cTECs) et médullaires (mTECs) ont un taux de prolifération similaire chez les jeunes souris, mais chez l’adulte, les cTECs prolifèrent plus lentement que les mTECs; (2) les TECs prolifèrent plus rapidement chez les souris jeunes que adultes; (3) des LRC sont détectées chez l’adulte, mais pas chez les jeunes souris. Les LRC, retrouvées dans le compartiment cTEC, sous-expriment des gènes associés à la sénescence et surexpriment des gènes importants pour le développement et le renouvellement des TECs. Ces résultats montrent que ces cellules sont quiescentes et suggèrent qu’elles pourraient bel et bien être les progéniteurs thymiques responsables du renouvellement des TECs adultes. / The thymus undergoes a rapid degeneration with age termed thymic involution that causes a loss of function of the thymus with age. To this day, mechanisms of thymic maintenance are still unknown. This is why we aimed to identify thymic epithelial stem cells. Since stem cells are quiescent in many tissues in adults, our main objectives were to determine whether the thymic epithelium contains quiescent cells and study the proliferation kinetics of thymic epithelial cells in neonatal and adult mice. To this end, we used the transgenic mouse model H2B-GFP Tet-On, a label-retaining assay allowing us to identify cells that have not divided for a prolonged period of time, which are called label-retaining cells (LRC). First, we showed that in the adult thymus, females’ thymic epithelial cells (TECs) proliferated more actively than males’ TECs. We observed three main differences between neonatal and adult thymi: (1) cTECs and mTECs have similar proliferation rates in young, but mTECs cycled more actively in adult mice; (2) neonatal TECs have a higher turnover rate than adult’s TECs, and (3) we were able to detect LRC in adult mice, but not in neonatal mice. These LRC are contained in the cTEC compartment and express very low levels of senescence-associated proteins and show a high expression of genes important for thymic development and. These results show that the LRC identified in adult thymi are not senescent cells and therefore might represent the elusive thymic progenitor cells responsible for thymic maintenance and regeneration in adult mice.
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Le stress protéotoxique : le prix à payer pour la tolérance au soi immunitaireSt-Pierre, Charles 03 1900 (has links)
No description available.
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Cellules souches, hormones sexuelles et régénération thymiqueDumont-Lagacé, Maude 08 1900 (has links)
No description available.
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Investigating the thymopoiesis stimulating property of interleukin-21 in aging miceAl-Chami, Edouard 04 1900 (has links)
La vaccination est largement utilisée pour la génération de lymphocytes T spécifiques contre les
tumeurs. Malheureusement, cette stratégie n'est pas adaptée aux personnes âgées car leur thymus
régresse avec l'âge conduisant ainsi à une baisse dans la production de cellules T et à
l'accumulation de cellules immunitaires âgées ayant des défauts liés à leurs stimulations. Comme
il a été démontré auparavant que L’IL-21 est capable d’induire des fonctions thymiques, nous
avons émis l’hypothèse que l’injection d’IL-21 à des souris âgées stimulera la thymopoïèse. Nos
résultats montrent que l’administration de l’IL-21 augmente le nombre absolu de thymocytes
chez les souris âgées et augmente la migration de ces cellules vers la périphérie ou ils contribuent
à la diversité du TCR. De plus les cellules T en périphérie expriment un niveau plus élevé de
miR181-a, et par conséquent moins de phosphatase comme SHP2, DUSP5/6 qui inhibent le
TCR. En vaccinant des souris âgées avec le peptide Trp2, les souris traitées avec l’IL-21
montrent un retard dans la croissance des cellules B16 tumorales. Cette étude montre que l’IL-21
pourrait être utilisé comme stratégie pour le rétablissement du systeme immunitaire chez les
personnes âgées. / Vaccines have been largely sought for the generation of protective tumor-specific T cells.
Unfortunately however, this strategy is not suitable for the elderly as their thymus regresses with
age leading to a decline in T-cell production and accumulation of aged lymphocytes endowed
with stimulation-related defects. Interleukin (IL)-21 has been shown to display thymostimulatory
properties. Therefore, we hypothesized that IL-21 administration to ageing host may
boost T-cell production and restore a competent peripheral T-cell compartment. Our study shows
that IL-21 injection to aged mice lead to an increase in the thymocytes absolute number and an
increase in thymocytes egress to the periphery where they enhance the T-cell receptor (TCR)
diversity. Furthermore T-cell in the periphery express higher level of miR-181a and thus less
TCR-inhibiting phosphatases SHP-2 and DUSP5/6 enable them to be more responsive upon
stimulation. Consequently, aged rIL-21-treated mice vaccinated using a tyrosinase-related
protein 2 (Trp2)-derived peptide exhibited a substantial delay in B16 tumor growth and
improved survival. The results of this study highlight the immunorestorative function of rIL-21
paving its use as a strategy for the re-establishment of effective immunity in the elderly.
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