The thymus provides the physiological microenvironment critical for the development of T lymphocytes, the cells that orchestrate the adaptive immune system to generate an antigen‐specific response. A ...diverse population of stroma cells provides surface‐bound and soluble molecules that orchestrate the intrathymic maturation and selection of developing T cells. Forming an intricate 3D architecture, thymic epithelial cells (TEC) represent the most abundant and important constituent of the thymic stroma. Effective models for in and ex vivo use of adult TEC are still wanting, limiting the engineering of functional thymic organoids and the understanding of the development of a competent immune system. Here a 3D scaffold is developed based on decellularized thymic tissue capable of supporting in vitro and in vivo thymopoiesis by both fetal and adult TEC. For the first time, direct evidences of feasibility for sustained graft‐resident T‐cell development using adult TEC as input are provided. Moreover, the scaffold supports prolonged in vitro culture of adult TEC, with a retained expression of the master regulator Foxn1. The success of engineering a thymic scaffold that sustains adult TEC function provides unprecedented opportunities to investigate thymus development and physiology and to design and implement novel strategies for thymus replacement therapies.
A novel 3D scaffold derived from the thymic extracellular matrix seeded in vitro by either fetal or adult thymic epithelial cells (TEC) supports thymopoiesis over an extended period of time. The success of engineering a thymic scaffold sustaining TEC function provides unprecedented opportunities to investigate thymus development and physiology ex vivo and to design and implement novel strategies for thymus replacement therapies.
During acute graft-versus-host disease (aGVHD) in mice, autoreactive T cells can be generated de novo in the host thymus implying an impairment in self-tolerance induction. As a possible mechanism, ...we have previously reported that mature medullary thymic epithelial cells (mTEChigh) expressing the autoimmune regulator are targets of donor T-cell alloimmunity during aGVHD. A decline in mTEChigh cell pool size, which purges individual tissue-restricted peripheral self-antigens (TRA) from the total thymic ectopic TRA repertoire, weakens the platform for central tolerance induction. Here we provide evidence in a transgenic mouse system using ovalbumin (OVA) as a model surrogate TRA that the de novo production of OVA-specific CD4+ T cells during acute GVHD is a direct consequence of impaired thymic ectopic OVA expression in mTEChigh cells. Our data, therefore, indicate that a functional compromise of the medullary mTEChigh compartment may link alloimmunity to the development of autoimmunity during chronic GVHD.
•Loss of thymic ectopic self-antigen expression during murine acute GVHD is responsible for the de novo generation of autoreactive T cells.•Functional impairment of the thymus medulla mechanistically links acute GVHD to posttransplantation autoimmunity.
The autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disorder caused by mutations in
AIRE,
the autoimmune-regulator gene. The authors identified reactivity to the NACHT ...leucine-rich-repeat protein 5 (NALP5) by immunoscreening a human parathyroid complementary DNA library, using serum samples from patients with APS-1 and hypoparathyroidism. The findings suggest that NALP5 is a tissue-specific autoantigen involved in hypoparathyroidism in patients with APS-1.
The authors identified reactivity to the NACHT leucine-rich-repeat protein 5 (NALP5) using serum samples from patients with autoimmune polyendocrine syndrome type 1 and hypoparathyroidism. The findings suggest that NALP5 is a tissue-specific autoantigen in these patients.
Autoimmune polyendocrine syndrome type 1 (APS-1) (Online Mendelian Inheritance in Man number 240300) is a rare autosomal recessive disorder that develops in early childhood and results in tissue-specific multiorgan autoimmunity, leading to the hypofunction of multiple glands.
1
Endocrine organs such as the adrenal cortex, ovaries, and parathyroid glands are typically affected, resulting in a variety of clinical diseases, including hypocortisolism, hypoaldosteronism, delayed puberty, premature ovarian failure, and hypoparathyroidism with life-threatening hypocalcemia.
2
APS-1 is clinically defined as the presence of at least two components of the classic triad of hypoparathyroidism, adrenal insufficiency, and mucocutaneous candidiasis.
APS-1 is caused by mutations in . . .
Age-related thymopoietic insufficiency has been proposed to be related to either defects in lymphohematopoietic progenitors or the thymic microenvironment. In this study, we examined whether ...keratinocyte growth factor (KGF), an epithelial cell–specific growth factor, could increase thymopoietic capacity in aged mice by restoration of the function of thymic epithelial cells (TECs). The thymic cellularity in KGF-treated aged mice increased about 4-fold compared to placebo-treated mice, resulting in an equivalent thymic cellularity to young mice. Enhanced thymopoiesis was maintained for about 2 months after a single course of KGF, and sustained improvement was achieved by administration of monthly courses of KGF. With the enhanced thymopoiesis after KGF treatment, the number of naive CD4 T cells in the periphery and T-cell–dependent antibody production improved in aged mice. KGF induced increased numbers of TECs and intrathymic interleukin-7 (IL-7) production and reorganization of cortical and medullary architecture. Furthermore, KGF enhanced thymopoiesis and normalized TEC organization in klotho (kl/kl) mice, a model of premature degeneration and aging, which displays thymopoietic defects. The result suggests that TEC damage is pathophysiologically important in thymic aging, and KGF therapy may be clinically useful in improving thymopoiesis and immune function in the elderly.
Intrathymic T-cell development is critically dependent on cortical and medullary thymic epithelial cells (TECs). Both epithelial subsets originate during early thymus organogenesis from progenitor ...cells that express the thymoproteasome subunit beta 5t, a typical feature of cortical TECs. Using in vivo lineage fate mapping, we demonstrate in mice that beta 5t super(+) TEC progenitors give rise to the medullary TEC compartment early in life but significantly limit their contribution once the medulla has completely formed. Lineage-tracing studies at single cell resolution demonstrate for young mice that the postnatal medulla is expanded from individual beta 5t super(+) cortical progenitors located at the cortico-medullary junction. These results therefore not only define a developmental window during which the expansion of medulla is efficiently enabled by progenitors resident in the thymic cortex, but also reveal the spatio-temporal dynamics that control the growth of the thymic medulla. The thymus medulla is subject to a dramatic expansion during the first weeks of life. Using inducible TEC-specific lineage-tracing, Mayer et al. found that single beta 5t super(+) epithelial progenitor cells located at the cortico-medullary junction adopt a medullary TEC fate and actively contribute to this postnatal growth.
Thymic T cell development and T cell receptor repertoire selection are dependent on essential molecular cues provided by thymic epithelial cells (TEC). TEC development and function are regulated by ...their epigenetic landscape, in which the repressive H3K27me3 epigenetic marks are catalyzed by polycomb repressive complex 2 (PRC2). Here we show that a TEC-targeted deficiency of PRC2 function results in a hypoplastic thymus with reduced ability to express antigens and select a normal repertoire of T cells. The absence of PRC2 activity reveals a transcriptomically distinct medullary TEC lineage that incompletely off-sets the shortage of canonically-derived medullary TEC whereas cortical TEC numbers remain unchanged. This alternative TEC development is associated with the generation of reduced TCR diversity. Hence, normal PRC2 activity and placement of H3K27me3 marks are required for TEC lineage differentiation and function and, in their absence, the thymus is unable to compensate for the loss of a normal TEC scaffold.
Medullary thymic epithelial cells (mTECs) are specialized for inducing central immunological tolerance to self-antigens. To accomplish this, mTECs must adopt a mature phenotype characterized by ...expression of the autoimmune regulator Aire, which activates the transcription of numerous genes encoding tissue-restricted self-antigens. The mechanisms that control mature Aire
+ mTEC development in the postnatal thymus remain poorly understood. We demonstrate here that, although either CD4
+ or CD8
+ thymocytes are sufficient to sustain formation of a well-defined medulla, expansion of the mature mTEC population requires autoantigen-specific interactions between positively selected CD4
+ thymocytes bearing autoreactive T cell receptor (TCR) and mTECs displaying cognate self-peptide-MHC class II complexes. These interactions also involve the engagement of CD40 on mTECs by CD40L induced on the positively selected CD4
+ thymocytes. This antigen-specific TCR-MHC class II-mediated crosstalk between CD4
+ thymocytes and mTECs defines a unique checkpoint in thymic stromal development that is pivotal for generating a mature mTEC population competent for ensuring central T cell tolerance.
The systemic administration of keratinocyte growth factor (KGF) enhances T-cell lymphopoiesis in normal mice and mice that received a bone marrow transplant. KGF exerts protection to thymic stromal ...cells from cytoablative conditioning and graft-versus-host disease–induced injury. However, little is known regarding KGF's molecular and cellular mechanisms of action on thymic stromal cells. Here, we report that KGF induces in vivo a transient expansion of both mature and immature thymic epithelial cells (TECs) and promotes the differentiation of the latter type of cells. The increased TEC numbers return within 2 weeks to normal values and the microenvironment displays a normal architectural organization. Stromal changes initiate an expansion of immature thymocytes and permit regular T-cell development at an increased rate and for an extended period of time. KGF signaling in TECs activates both the p53 and NF-κB pathways and results in the transcription of several target genes necessary for TEC function and T-cell development, including bone morphogenetic protein 2 (BMP2), BMP4, Wnt5b, and Wnt10b. Signaling via the canonical BMP pathway is critical for the KGF effects. Taken together, these data provide new insights into the mechanism(s) of action of exogenous KGF on TEC function and thymopoiesis.
Emerging strategies to boost thymic function Holländer, Georg A; Krenger, Werner; Blazar, Bruce R
Current opinion in pharmacology,
08/2010, Letnik:
10, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The thymus constitutes the primary lymphoid organ for the generation of T cells. Its function is particularly susceptible to various negative influences ranging from age-related involution to atrophy ...as a consequence of malnutrition, infection or harmful iatrogenic influences such as chemotherapy and radiation. The loss of regular thymus function significantly increases the risk for infections and cancer because of a restricted capacity for immune surveillance. In recent years, thymus-stimulatory, thymus-regenerative, and thymus-protective strategies have been developed to enhance and repair thymus function in the elderly and in individuals undergoing hematopoietic stem cell transplantation. These strategies include the use of sex steroid ablation, the administration of growth and differentiation factors, the inhibition of p53, and the transfer of T cell progenitors to alleviate the effects of thymus dysfunction and consequent T cell deficiency.
Development of acute graft-versus-host disease (aGVHD) predisposes to chronic GVHD with autoimmune manifestations. A characteristic of experimental aGVHD is the de novo generation of autoreactive T ...cells. Central tolerance is dependent on the intrathymic expression of tissue-restricted peripheral self-antigens (TRA), which is in mature medullary thymic epithelial cells (mTEChigh) partly controlled by the autoimmune regulator (Aire). Because TECs are targets of donor T-cell alloimmunity, we tested whether murine aGVHD interfered with the capacity of recipient Aire+mTEChigh to sustain TRA diversity. We report that aGVHD weakens the platform for central tolerance induction because individual TRAs are purged from the total repertoire secondary to a decline in the Aire+mTEChigh cell pool. Peritransplant administration of an epithelial cytoprotective agent, fibroblast growth factor-7, maintained a stable pool of Aire+mTEChigh, with an improved TRA transcriptome despite aGVHD. Taken together, our data provide a mechanism for how autoimmunity may develop in the context of antecedent alloimmunity.
•Acute GVHD predisposes to autoimmune chronic GVHD, but it is currently unclear how autoimmunity is linked to antecedent alloimmunity.•Loss of central tolerance induction that occurs via functional compromise of thymic epithelial cells may provide such a pathogenic link.
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