NF-κB–Inducing Kinase in Thymic Stroma Establishes Central Tolerance by Orchestrating Cross-Talk with Not Only Thymocytes but Also Dendritic Cells

Mouri, Yasuhiro; Nishijima, Hitoshi; Kawano, Hiroshi; Hirota, Fumiko; Sakaguchi, Nobuo; Morimoto, Junko; Matsumoto, Machiko

doi:10.4049/jimmunol.1400389

Cited by 41 publications

(41 citation statements)

References 47 publications

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“…Thus, the lack of autoimmunity in the report by Birnberg et al, was attributed to the presence of pDCs and epidermal Langerhans cells (LCs) that were absent in the experimental system used by Ohnmacht et al in which DC ablation correlated with development of fatal autoimmunity [16, 17]. Similarly, mouse models with mutations affecting signaling through the NFkB pathway such as the alymphoplasia ( aly/aly ) mice develop chronic autoimmunity resembling Sjorgren’s syndrome despite impaired mTEC development and reduced numbers of tDC subsets [30, 31], again suggesting that severe disruptions of more than one subsets of thymic APCs are required for development of autoimmunty. Consistent with this, it was shown that depletion of DCs down to 5% of physiologic levels can still efficiently induce tolerance [32].…”

Section: Discussionmentioning

confidence: 99%

Medullary thymic epithelial cells and CD8α + dendritic cells coordinately regulate central tolerance but CD8α + cells are dispensable for thymic regulatory T cell production

Herbin

Bonito

Jeong

et al. 2016

Journal of Autoimmunity

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In the thymus, antigen presenting cells (APCs) namely, medullary thymic epithelial cells (mTECs) and thymic dendritic cells (tDCs) regulate T cell tolerance through elimination of autoreactive T cells and production of thymic T regulatory (tTreg) cells. How the different APCs in the thymus share the burden of tolerazing the emerging T cell repertoire remains unclear. For example, while mutations that inhibit mTEC development or function associate with peripheral autoimmunity, the role of tDCs in organ-specific autoimmunity and tTreg cell production remains controversial. In this report we used mice depleted of mTECs and/or CD8α+ DCs, to examine the contributions of these cell populations in thymic tolerance. We found that while mice depleted of CD8α+ DCs or mTECs were normal or developed liver inflammation respectively, combined depletion of mTECs and CD8α+ DCs resulted in overt peripheral autoimmunity. The autoimmune manifestations in mice depleted of both mTECs and CD8α+ cDCs associated with increased percentages of CD4+ and CD8+ T cells in the thymus. In contrast, while mTEC depletion resulted in reduced percentages of tTreg cells, no additional effect was observed when CD8α+ DCs were also depleted. These results reveal that: 1) mTECs and CD8α+ DCs cooperatively safeguard against peripheral autoimmunity through thymic T cell deletion; 2) CD8α+ DCs are dispensable for tTreg cell production, whereas mTECs play a non-redundant role in this process; 3) mTECs and CD8α+ DCs make unique contributions to tolerance induction that cannot be compensated for by other thymic APCs such as migratory SIRPα+ or plasmacytoid DCs.

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Section: Discussionmentioning

confidence: 99%

Medullary thymic epithelial cells and CD8α + dendritic cells coordinately regulate central tolerance but CD8α + cells are dispensable for thymic regulatory T cell production

Herbin

Bonito

Jeong

et al. 2016

Journal of Autoimmunity

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“…Real-time PCR for quantification of salivary protein 1, C-reactive protein, and Hprt was performed as described previously (14).…”

Section: Real-time Pcrmentioning

confidence: 99%

Aire Expression Is Inherent to Most Medullary Thymic Epithelial Cells during Their Differentiation Program

Kawano

Nishijima

Morimoto

et al. 2015

The Journal of Immunology

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Aire in medullary thymic epithelial cells (mTECs) plays an important role in the establishment of self-tolerance. Because Aire+ mTECs appear to be a limited subset, they may constitute a unique lineage(s) among mTECs. An alternative possibility is that all mTECs are committed to express Aire in principle, but Aire expression by individual mTECs is conditional. To investigate this issue, we established a novel Aire reporter strain in which endogenous Aire is replaced by the human AIRE-GFP-Flag tag (Aire/hAGF-knockin) fusion gene. The hAGF reporter protein was produced and retained very efficiently within mTECs as authentic Aire nuclear dot protein. Remarkably, snapshot analysis revealed that mTECs expressing hAGF accounted for >95% of mature mTECs, suggesting that Aire expression does not represent a particular mTEC lineage(s). We confirmed this by generating Aire/diphtheria toxin receptor–knockin mice in which long-term ablation of Aire+ mTECs by diphtheria toxin treatment resulted in the loss of most mature mTECs beyond the proportion of those apparently expressing Aire. These results suggest that Aire expression is inherent to all mTECs but may occur at particular stage(s) and/or cellular states during their differentiation, thus accounting for the broad impact of Aire on the promiscuous gene expression of mTECs.

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“…Both cell types are functionally and phenotypically different. The mTEC together with DC have a special roll in eliminating auto-reactive T-cell clones through negative selection, as well as helping to regulate the production of regulatory T (T reg ) cells involved in prevention of autoimmune responses (Osada et al 2006;Mouri et al 2014;Ucar & Rattay 2015).…”

Section: Introductionmentioning

confidence: 99%

Thymic cytoarchitecture changes in mice exposed to vanadium

Ustarroz-Cano¹,

García-Peláez²,

Cervantes-Yépez³

et al. 2017

Journal of Immunotoxicology

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The thymus is a vital immune system organ wherein selection of T-lymphocytes occurs in a process regulated by dendritic and epithelial thymic cells. Previously, we have reported that in a mouse model of vanadium inhalation, a decrease in CD11c dendritic cells was observed. In the present study, we report on a thymic cortex-medulla distribution distortion in these hosts due to apparent effects of the inhaled vanadium on cytokeratin-5 (K5 þ ) epithelial cells in the same mouse model -after 1, 2, and 4 weeks of exposure -by immunohistochemistry. These cells -together with dendritic cells -eliminate autoreactive T-cell clones and regulate the production of regulatory T-cells in situ. Because both cell types are involved in the negative selection of autoreactive clones, a potential for an increase in development of autoimmune conditions could be a possible consequence among individuals who might be exposed often to vanadium in air pollution, including dwellers of highly polluted cities with elevated levels of particulate matter onto which vanadium is often adsorbed. ARTICLE HISTORY

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NF-κB–Inducing Kinase in Thymic Stroma Establishes Central Tolerance by Orchestrating Cross-Talk with Not Only Thymocytes but Also Dendritic Cells

Cited by 41 publications

References 47 publications

Medullary thymic epithelial cells and CD8α + dendritic cells coordinately regulate central tolerance but CD8α + cells are dispensable for thymic regulatory T cell production

Medullary thymic epithelial cells and CD8α + dendritic cells coordinately regulate central tolerance but CD8α + cells are dispensable for thymic regulatory T cell production

Aire Expression Is Inherent to Most Medullary Thymic Epithelial Cells during Their Differentiation Program

Thymic cytoarchitecture changes in mice exposed to vanadium

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