RANK signaling induces interferon-stimulated genes in the fetal thymic stroma

Ohshima, Daisuke; Qin, Junwen; Konno, Hiroyasu; Hirosawa, Akihisa; Shiraishi, Takuma; Yanai, H.; Shimo, Yusuke; Shinzawa, Miho; Akiyama, Nobuko; Yamashita, Riu; Nakai, Kenta; Akiyama, Taishin; Inoue, Jun

doi:10.1016/j.bbrc.2011.04.049

Cited by 13 publications

(11 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent work has suggested that genetic defects in genes other than Aire (e.g., CCR7, RANK-L, TRAF6, Bim) also may affect central tolerance to thymic TSAs (31)(32)(33)(34). Application of our P2-specific tetramer reagent in such mutant strains and in other models that invoke defects in central tolerance will allow for a more refined assessment of their potential effect in the maintenance of thymic tolerance.…”

Section: Discussionmentioning

confidence: 99%

Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection

Taniguchi

DeVoss

Moon

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

119

View full text Add to dashboard Cite

The autoimmune regulator (Aire) plays a critical role in central tolerance by promoting the display of tissue-specific antigens in the thymus. To study the influence of Aire on thymic selection in a physiological setting, we used tetramer reagents to detect autoreactive T cells specific for the Aire-dependent tissue-specific antigen interphotoreceptor retinoid-binding protein (IRBP), in the polyclonal repertoire. Two class II tetramer reagents were designed to identify T cells specific for two different peptide epitopes of IRBP. Analyses of the polyclonal T-cell repertoire showed a high frequency of activated T cells specific for both IRBP tetramers in Aire −/− mice, but not in Aire +/+ mice. Surprisingly, although one tetramer-binding T-cell population was efficiently deleted in the thymus in an Aire-dependent manner, the second tetramer-binding population was not deleted and could be detected in both the Aire −/− and Aire +/+ T-cell repertoires. We found that Aire-dependent thymic deletion of IRBP-specific T cells relies on intercellular transfer of IRBP between thymic stroma and bone marrow-derived antigen-presenting cells. Furthermore, our data suggest that Aire-mediated deletion relies not only on thymic expression of IRBP, but also on proper antigen processing and presentation of IRBP by thymic antigen-presenting cells.autoimmunity | uveitis T hymic tolerance mechanisms play an important role in preventing autoimmunity. A key mediator in thymic tolerance is the Autoimmune Regulator (Aire), a transcriptional regulator that is highly expressed in medullary thymic epithelial cells (mTECs) (1). Aire promotes the expression of peripheral tissuespecific self-antigens (TSAs) in mTECs for the purpose of tolerizing self-reactive T cells to these TSAs. Both patients and mice with defects in Aire develop multiorgan autoimmunity, reinforcing the importance of this process in controlling immune tolerance (2). Several organ-specific autoimmune diseases in the Aire-deficient model can be linked to a failure in the appropriate thymic expression of a given TSA under the control of Aire (3-6). Autoimmunity in the eyes of Aire-deficient mice arises as a response against the retina-specific protein interphotoreceptor retinoid binding protein (IRBP) (3). IRBP is expressed in the thymus in an Aire-dependent fashion, and thymic transfer of IRBP-deficient thymi into athymic (nude) WT hosts is sufficient to induce posterior uveitis (3).To date, the detection of Aire-mediated thymic negative selection has relied on the use of T-cell receptor (TCR) transgenic mice (7,8). In these TCR transgenic models, the TCRs are specific for model foreign antigens, and "neo"-self antigen expression is provided by a second transgene where the model antigen is expressed under the control of a tissue-specific promoter that results in mTEC expression. Although such transgenic models have been instructive in demonstrating the potential role of Aire in negative selection, the physiological meaning of these studies is limited by a number of factors, inc...

show abstract

Section: Discussionmentioning

confidence: 99%

Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection

Taniguchi

DeVoss

Moon

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

119

View full text Add to dashboard Cite

show abstract

“…In a recent study [64], in vitro RANK stimulation of mTEC progenitors was shown to result in the upregulation of various interferon (IFN)-stimulated genes (ISGs) via a mechanism involving phosphorylation of signal transducer and activator of transcription (STAT)1; a process that also occurs following the binding of type I IFNs to their receptors. Interestingly, RANK signalling in mTECs has been found to induce Ifnb expression, a gene known to be dependent upon Aire expression, thereby providing an explanation for the RANK-dependent induction of ISGs in developing mTECs.…”

Section: Reviewmentioning

confidence: 99%

“…Interestingly, RANK signalling in mTECs has been found to induce Ifnb expression, a gene known to be dependent upon Aire expression, thereby providing an explanation for the RANK-dependent induction of ISGs in developing mTECs. Although the importance of the induction of ISGs in mTEC development and function is currently unclear, it is interesting to note that such genes are involved in a diverse range of cellular processes including apoptosis and mRNA/protein modifications [64], which may link to the importance of TRA expression by Aire + mTECs during tolerance induction.…”

Section: Reviewmentioning

confidence: 99%

Thymic epithelial cells: working class heroes for T cell development and repertoire selection

Anderson

Takahama

2012

Trends in Immunology

298

331

View full text Add to dashboard Cite

“…Signaling through TLR-3, -4, -7, and -9 as well as the RIG-I-like receptors can induce rapid and robust IFN-I production in response to infection (2). Interestingly, recent studies have hinted that the TNFR superfamily (TNFRSF) members, TNFR-1, TNFR-2, receptor activator for NF-kB (RANK), and lymphotoxin (LT)-b receptor (LTbR), are also capable of inducing IFN-I production; however, in contrast to PRR activation, TNFRSF members typically elicit a very modest, albeit sustained level of IFN-I production (19)(20)(21)(22)(23).…”

mentioning

confidence: 99%

A Lymphotoxin/Type I IFN Axis Programs CD8+ T Cells To Infiltrate a Self-Tissue and Propagate Immunopathology

Maître

Cummings

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Type I IFNs (IFN-I) are cytokines that can mediate both immune suppression and activation. Dendritic cells (DC) are significant producers of IFN-I, and depending on the context (nature of Ag, duration of exposure to Ag), DC-derived IFN-I can have varying effects on CD8+ T cell responses. In this study, we report that in the context of a CD8+ T cell response to a self-Ag, DC-intrinsic expression of IFN regulatory factor 3 is required to induce optimal proliferation and migration of autoreactive CD8+ T cells, ultimately determining their ability to infiltrate a target tissue (pancreas), and the development of glucose intolerance in rat insulin promoter–glycoprotein (RIP-GP) mice. Moreover, we show that signals through the lymphotoxin-β receptor (LTβR) in DC are also required for the proliferation of autoreactive CD8+ T cells, the upregulation of VLA4/LFA1 on activated CD8+ T cells, and their subsequent infiltration into the pancreas both in vitro and in vivo. Importantly, the defects in autoreactive CD8+ T cell proliferation, accumulation of CD8+ T cells in the pancreas, and consequent glucose intolerance observed in the context of priming by LTβR−/− DC could be rescued by exogenous addition of IFN-I. Collectively, our data demonstrate that the LTβR/IFN-I axis is essential for programming of CD8+ T cells to mediate immunopathology in a self-tissue. A further understanding of the IFN-I/LTβR axis will provide valuable therapeutic insights for treatment of CD8+ T cell–mediated autoimmune diseases.

show abstract

RANK signaling induces interferon-stimulated genes in the fetal thymic stroma

Cited by 13 publications

References 23 publications

Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection

Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection

Thymic epithelial cells: working class heroes for T cell development and repertoire selection

A Lymphotoxin/Type I IFN Axis Programs CD8+ T Cells To Infiltrate a Self-Tissue and Propagate Immunopathology

Contact Info

Product

Resources

About