Lymphotoxin pathway directs thymic Aire expression

Chin, Robert; Lo, James C.; Kim, Oliver; Blink, Sarah E.; Christiansen, Peter A.; Peterson, Pärt; Wang, Yan; Ware, Carl F.; Fu, Yang–Xin

doi:10.1038/ni982

Cited by 180 publications

(194 citation statements)

References 30 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: 79%

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: 79%

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

et al. 2008

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“…The profound reduction of the MTEC compartment in the RelB Ϫ/Ϫ thymus encompasses a dramatic loss of Aire expression and a paucity of UEA ϩ MTEC (41,42), while deficiencies of signaling pathways that regulate RelB expression variably recapitulate the RelB Ϫ/Ϫ thymic phenotype. Thymi from mice deficient in TNFR-associated factor 6 (43), NF-B-inducing kinase (44), or I B kinase ␣ (45) closely resemble the RelB Ϫ/Ϫ thymus, while the thymic phenotype of LT␣R/LT␤R-deficient mice is less severe (46,47) and CD40 Ϫ/Ϫ thymi appear to be normal (referenced in Ref. 44).…”

Section: Discussionmentioning

confidence: 99%

Aire-Dependent Alterations in Medullary Thymic Epithelium Indicate a Role for Aire in Thymic Epithelial Differentiation

Gillard¹,

Dooley²,

Erickson³

et al. 2007

The Journal of Immunology

116

113

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The prevalent view of thymic epithelial differentiation and Aire activity holds that Aire functions in terminally differentiated medullary thymic epithelial cells (MTECs) to derepress the expression of structural tissue-restricted Ags, including pancreatic endocrine hormones. An alternative view of these processes has proposed that Aire functions to regulate the differentiation of immature thymic epithelial cells, thereby affecting tissue-restricted Ag expression and negative selection. In this study, we demonstrate that Aire impacts several aspects of murine MTECs and provide support for this second model. Expression of transcription factors associated with developmental plasticity of progenitor cells, Nanog, Oct4, and Sox2, by MTECs was Aire dependent. Similarly, the transcription factors that regulate pancreatic development and the expression of pancreatic hormones are also expressed by wild-type MTECs in an Aire-dependent manner. The altered transcriptional profiles in Aire-deficient MTECs were accompanied by changes in the organization and composition of the medullary epithelial compartment, including a reduction in the medullary compartment defined by keratin (K) 14 expression, altered patterns of K5 and K8 expression, and more prominent epithelial cysts. These findings implicate Aire in the regulation of MTEC differentiation and the organization of the medullary thymic compartment and are compatible with a role for Aire in thymic epithelium differentiation.

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“…This suggests that the Ins2 increase seen in the mTECs requires the direct interaction between the two cell types and this effect may be mediated by Aire, whose expression increased coordinately with Ins2. Lymphotoxin beta receptor (TNFR superfamily, member 3) (LTβR), known to upregulate both Aire and Ins2 [27,43] may play a role here, in conjunction with interactions that may involve additional co-receptors between mTECs and thymocytes.…”

Section: Discussionmentioning

confidence: 99%

Regulation of insulin gene expression by cytokines and cell–cell interactions in mouse medullary thymic epithelial cells

Levi

Polychronakos

2009

Diabetologia

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Aims/hypothesis The expression of tissue-specific selfantigens in the thymus is essential for self-tolerance. Genetic susceptibility to type 1 diabetes correlates inversely with thymic insulin expression and, in mice, lowered levels of this expression result in T cell responses against insulin. This study was undertaken to examine whether thymic insulin expression is regulated by the same metabolic stimuli as in beta cells or by different inputs, possibly of an immune nature. Methods Ins2 mRNA changes in mouse thymus were evaluated in vivo, following intraperitoneal glucose injection. We also examined the effect of a high glucose concentration on Ins2 mRNA in clones of insulin-expressing medullary thymus epithelial cell lines (mTECs). The same in vitro system was used to evaluate the effect of IFN-γ and cell-tocell contact with thymocytes in co-culture. Results Ins2 mRNA was significantly increased in the pancreas following a glucose load, but remained unchanged in the thymus. Furthermore, stimulation of insulin-expressing mTECs in vitro with IFN-γ, a cytokine involved in T cell negative selection, decreased levels of insulin expression even though expression of Aire was increased. Last, coculture of mTECs with thymocytes resulted in an upregulation of both Aire and insulin expression. Conclusions/interpretation We conclude that regulation of insulin transcription in the thymus is not dependent on metabolic stimuli but it may, instead, be under the control of cytokines and cell-to-cell interactions with lymphoid cells. That this regulation is not always coordinated with that of Aire, a non-specific master switch, suggests insulinspecific mechanisms.

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Lymphotoxin pathway directs thymic Aire expression

Cited by 180 publications

References 30 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)

Aire-Dependent Alterations in Medullary Thymic Epithelium Indicate a Role for Aire in Thymic Epithelial Differentiation

Regulation of insulin gene expression by cytokines and cell–cell interactions in mouse medullary thymic epithelial cells

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