The Lymphotoxin Pathway Regulates Aire-Independent Expression of Ectopic Genes and Chemokines in Thymic Stromal Cells

Seach, Natalie Louise; Ueno, Tomoo; Fletcher, Anne L.; Lowen, Tamara Eve; Mattesich, Monika; Engwerda, Christian R.; Scott, Hamish S.; Ware, Carl F.; Chidgey, Ann Patricia; Gray, Daniel H.D.; Boyd, Richard

doi:10.4049/jimmunol.180.8.5384

Cited by 98 publications

(104 citation statements)

References 35 publications

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“…These mice have significantly reduced levels of Aire [20] and NKT cells [21,22], but relatively normal conventional T-cell numbers. A similar correlation between Aire expression and NKT cell numbers was reported in lymphotoxin-deficient mice [23,24], although the link between the expression of lymphotoxin and Aire-dependent genes has been disputed in more recent studies [25][26][27]. Human patients (and a mouse model) of Omenn syndrome [28,29] also have reduced levels of Aire and NKT cells and it is interesting to note that the severe NKT cell deficit evident in NOD mice coincides with significant morphological abnormalities among Aire 1 medullary cells in the thymus [20].…”

Section: Introductionsupporting

confidence: 55%

NKT cell development in the absence of the autoimmune regulator gene (Aire)

et al. 2008

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Autoimmune regulator gene (Aire)-deficient mice develop an array of autoimmune lesions that reflect failures of immune tolerance. Negative selection is clearly compromised in these mice, but there is evidence to suggest that other mechanisms of tolerance might also be affected, including a possible impairment of regulatory T cell (Treg) development. Studies to date have failed to demonstrate any significant impact on the development or function of the FOXP3 1 Treg compartment, but NKT cells represent a distinct regulatory cell lineage that also develop in the thymus and which are known to influence selftolerance. Aire-related defects coincide with NKT cell deficiencies in a number of animal models, but the direct consequence of Aire-deficiency on NKT cell development has not been established. In this study, we demonstrate that the frequency, distribution and cytokine production of NKT cells and their subsets is principally normal in Aire-deficient mice. We conclude that Aire has little or no effect on regulatory T cell development in general and NKT cells in particular.

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Section: Introductionsupporting

confidence: 55%

NKT cell development in the absence of the autoimmune regulator gene (Aire)

et al. 2008

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“…LT signaling culminates in nuclear translocation of the RelB/ p52 dimer and results in transcription of genes critical for maintenance of secondary lymphoid organs and the mTEC network, including CCL19, CCL21, and CXCL13 (34,45,70). In this model, the increase in CCL19 and CCL21 was most likely due to dysregulated transcription rather than to increased LT signaling, since these chemokines were not increased uniformly across mTEC subsets.…”

Section: Discussionmentioning

confidence: 90%

Reduced Thymic Aire Expression and Abnormal NF-κB2 Signaling in a Model of Systemic Autoimmunity

Fletcher

Seach²,

Reiseger³

et al. 2009

The Journal of Immunology

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The thymic stromal niche normally directs the production and export of a self-tolerant T cell repertoire. Many models of spontaneous autoimmunity, however, develop thymic architectural abnormalities before disease onset. Although this is suspected to affect central tolerance induction, creating an autoimmune predisposition, in-depth analysis of the microenvironment within these thymi is lacking, such that the mechanisms and likely direct effects on the T cell repertoire are unknown or speculative. Here we show that NZB mice, the first described model for systemic autoimmunity, demonstrate a complex thymic phenotype, including a lack of the autoimmune regulator (Aire), early defects in thymic epithelial cell (TEC) expansion, and evidence for altered NF-κB2 signaling. Analysis of medullary TEC revealed a numerical loss of the Aire-expressing MHC class IIhigh (mTEC-high) subset as well reduced Aire protein and mRNA per cell. RelB expression was also reduced, while chemokines CCL19 and CCL21 were increased. Unexpectedly, the proportion of cortex and medulla in the NZB mice was normal from 36 wk, despite worsening architectural abnormalities. These data show that the NZB defect is more complex than previously appreciated, segregating into early numerical TEC deficiencies that correct with age, late degeneration of the niche architecture that does not affect TEC number, and a persistent reduction in Aire and RelB expression per cell acquired upon mTEC-high differentiation.

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“…In the postnatal thymus, the cellularity of Aire 1 mTEC is controlled by cooperation of CD40 and RANK signals mainly provided by CD4 1 SP thymocytes [36][37][38]. The TNF-related cytokines, lymphotoxin LTa/LTb and LTbR have also been recently shown to influence the proper organization and differentiation of mTEC without affecting the expression of Aire [39]. Since we have shown that Spatial expression strongly differs between immature and mature mTEC, we can suggest that its expression could be controlled by any of those signaling pathways (Fig.…”

Section: Rank Signals Regulate Spatial Expression Through the Transcrmentioning

confidence: 99%

Spatial (Tbata) expression in mature medullary thymic epithelial cells

et al. 2010

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The Spatial gene is expressed in highly polarized cell types such as testis germ cells, brain neurons and thymic epithelial cells (TEC). Its expression was documented in testis and brain but poorly characterized in thymus. Here, we characterize for the first time Spatial-expressing TEC throughout ontogeny and adult mouse thymus. Spatial is expressed in thymicfated domain by embryonic day E10.5 and persists in subcapsular, cortical, medullary epithelial cells and in MTS24 1 progenitor TEC. Using mouse strains in which thymocyte development is blocked at various stages, we show that Spatial expression is independent of thymocyte-derived signals during thymus organogenesis. Analyses on purified thymic cell subsets show that Spatial short isoforms are expressed in cortical TEC (cTEC) and mature medullary TEC (mTEC). Spatial long isoforms were detected in the same TEC population. Spatial presents a nuclear distribution specific to mature mTEC expressing UEA1 and Aire. Aire-and RANKL-deficient mice revealed that Spatial expression is drastically reduced in the thymus of these mutants. These findings reveal a critical function of Aire in regulating Spatial expression, which is compatible with promiscuous Spatial gene expression. 530 IntroductionThe vertebrate thymus is responsible for the production of functional nonautoreactive T lymphocytes. In this primary lymphoid organ, T-cell precursors commonly called thymocytes undergo a series of developmental stages through interactions with thymic stromal cells, resulting in the generation of mature T lymphocytes that are exported to the periphery [1,2]. The unique function of the thymus resides mainly in the thymic epithelium, which forms the major subcompartment of the stroma [3,4]. The thymic epithelium itself is commonly divided into two main regions, the cortex and the medulla, and each of these regions contains several ultrastructurally and phenotypically distinct types of thymic epithelial cells (TEC) [5,6]. TEC are required both for thymus organogenesis and for the promotion of most if not all stages of thymocyte maturation [3,4]. Understanding the molecular mechanisms regulating TEC differentiation and function provides crucial insights into mechanisms controlling T-cell development in the thymus.Using DNA chip technology we isolated the Spatial gene (Stromal Protein Associated with Thymii and Lymph node), also known as Tbata (thymus, brain and testes associated), by an approach based on differential screening between different knock-out mice models exhibiting distinct thymic immunodeficiencies [7]. This analysis led to the identification of three adult variants of the Spatial gene expressed in the thymus [8]. In addition, we also described two other isoforms isolated in the testis [8][9][10]. According to the size of alternative spliced variants, we have respectively named Spatial isoforms: Spatial-a (1035 bp), Spatial-b (1002 bp), Spatial-g (933 bp) for the short isoforms identified in the thymus; Spatial-d (1353 bp) and Spatial-e (1454 bp) for the long isoforms ...

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The Lymphotoxin Pathway Regulates Aire-Independent Expression of Ectopic Genes and Chemokines in Thymic Stromal Cells

Cited by 98 publications

References 35 publications

NKT cell development in the absence of the autoimmune regulator gene (Aire)

NKT cell development in the absence of the autoimmune regulator gene (Aire)

Reduced Thymic Aire Expression and Abnormal NF-κB2 Signaling in a Model of Systemic Autoimmunity

Spatial (Tbata) expression in mature medullary thymic epithelial cells

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