Aire suppresses CTLA-4 expression from the thymic stroma to control autoimmunity

Morimoto, Junko; Matsumoto, Minoru; Miyazawa, Ryuichiro; Yoshida, Hideyuki; Tsuneyama, Koichi

doi:10.1016/j.celrep.2022.110384

Cited by 19 publications

(16 citation statements)

References 60 publications

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“…Aire is expressed from a portion of mature CD80 high mTECs (23,24), and the percentages of Aire 1 mTECs were not also altered by the lack of Ly6C1/Ly6C2 (Fig. 1B).…”

Section: Dispensable Role Of Ly6c Proteins In Immune Homeostasismentioning

confidence: 86%

“…Thymic epithelial cells (TECs) were prepared via enzymatic digestion of thymi, and subjected to flow cytometric analysis using a FACSCalibur (BD Biosciences) and a FACSAria II (BD Biosciences) as described previously (21,23,24). In brief, TECs were defined as CD45 À epithelial cell adhesion molecule 1 (EpCAM) 1 cells, and mTECs were defined as CD45 À EpCAM 1 Ulex europaeus agglutinin 1 (UEA-1) 1 cells.…”

Section: Cell Preparation and Flow Cytometric Analysismentioning

confidence: 99%

“…We have previously reported that Gr-1 mAb (clone RB6-8C5), which recognizes Ly6G as an authentic Ag but cross-reacts with Ly6C, targets a unique subset of mTECs. mTECs are classified into immature mTECs (CD80 low mTECs) and mature mTECs (CD80 high mTECs) based on the expression levels of CD80 (23,24). By using the mAbs specific for Ly6C (clone HK1.4) and Ly6G (clone 1A8), we have demonstrated that Ly6C 1 /Ly6G À , Ly6C À /Ly6G 1 , and Ly6C 1 /Ly6G 1 subsets of mature CD80 high mTECs exist with various proportions depending on the genetic background of mice (i.e., 515% in total) (21).…”

Section: Dispensable Role Of Ly6c Proteins In Immune Homeostasismentioning

confidence: 99%

“…Because Ly6C is mainly expressed from mature CD80 high mTECs, and Ly6C 1 mTECs are absent in Aire-deficient mice (21), we further evaluated the differential expression of Ly6C1 and Ly6C2 after dividing the mature CD80 high mTECs into Aire 1 and Aire À mTECs (23,24). The percentages of Ly6C 1 mTECs from WT were higher in Aire 1 mTECs (13.2 6 0.5%) than Aire À mTECs (3.3 6 0.1%) (Fig.…”

Section: Differential Expression Of Ly6c1 and Ly6c2 From Immune Cellsmentioning

confidence: 99%

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No Major Impact of Two Homologous Proteins Ly6C1 and Ly6C2 on Immune Homeostasis

et al. 2022

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Ly6C comprises two homologous components of Ly6C1 and Ly6C2, and the expression of either of the Ly6C molecules defines unique functional subsets of monocytes. Ly6C is also expressed by other immune cell types, including Aire-expressing medullary thymic epithelial cells. Because the role of Ly6C expression in determining the functional subsets remains unclear, we generated mice deficient for both Ly6C1 and Ly6C2 with CRISPR-Cas9-mediated deletion. Mice deficient for Ly6C1/Ly6C2 showed no major alterations in the subsets and function of monocyte and other immune cells, including the cells involved in the dextran sulfate sodium salt-induced colitis model. By generating the mice deficient for Ly6C1 alone, we have also investigated the expression pattern of Ly6C1 and Ly6C2 in immune cells. Except for medullary thymic epithelial cells and CD4 single-positive T cells, immune cells predominantly expressed Ly6C2. Thus, despite the importance as a marker with a unique differential expression pattern, the Ly6C molecules have no major impact on determining the functional subsets and maintaining immune homeostasis. ImmunoHorizons, 2022, 6: 202-210.

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“…Aire is expressed from a portion of mature CD80 high mTECs (23,24), and the percentages of Aire 1 mTECs were not also altered by the lack of Ly6C1/Ly6C2 (Fig. 1B).…”

Section: Dispensable Role Of Ly6c Proteins In Immune Homeostasismentioning

confidence: 86%

Section: Cell Preparation and Flow Cytometric Analysismentioning

confidence: 99%

Section: Dispensable Role Of Ly6c Proteins In Immune Homeostasismentioning

confidence: 99%

Section: Differential Expression Of Ly6c1 and Ly6c2 From Immune Cellsmentioning

confidence: 99%

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No Major Impact of Two Homologous Proteins Ly6C1 and Ly6C2 on Immune Homeostasis

et al. 2022

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“…We speculate that altered heterogeneity of mTECs caused by the lack of Aire and augmented Aire may change in the expression of tolerance-relevant genes from mTECs, besides TRAs, such as chemokines 10 and co-stimulatory molecules. 21 Further studies are required to reveal the exact mechanisms underlying Airedependent thymic tolerance. How the defect in the thymic tolerance is linked to the higher susceptibility to EAE in 3xAire-KI also needs to be clarified.…”

Section: Discussionmentioning

confidence: 99%

Development of organ‐specific autoimmunity by dysregulated Aire expression

et al. 2022

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Deficiency for AIRE/Aire in both humans and mice results in the development of organ‐specific autoimmune disease. We tested whether augmented and/or dysregulated AIRE/Aire expression might be also prone to the breakdown of self‐tolerance. To define the effect of augmented Aire expression on the development of autoimmunity, antigen‐specific clonal deletion and production of clonotypic regulatory T cells (Tregs) in the thymus were examined using mice expressing two additional copies of Aire in a heterozygous state (3xAire‐knockin mice: 3xAire‐KI). We found that both clonal deletion of autoreactive T cells and production of clonotypic Tregs in the thymus from 3xAire‐KI were impaired in a T‐cell receptor‐transgenic system. Furthermore, 3xAire‐KI females showed higher scores of experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein than wild‐type littermates, suggesting that augmented Aire expression exacerbates organ‐specific autoimmunity under disease‐prone conditions. In humans, we found that one patient with amyopathic dermatomyositis showed CD3–CD19– cells expressing AIRE in the peripheral blood before the treatment but not during the remission phase treated with immunosuppressive drugs. Thus, not only loss of function of AIRE/Aire but also augmented and/or dysregulated expression of AIRE/Aire should be considered for the pathogenesis of organ‐specific autoimmunity. We suggest that further analyses should be pursued to establish a novel link between organ‐specific autoimmune disease and dysregulated AIRE expression in clinical settings.

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T‐cell selection in the thymus: New routes toward the identification of the self‐peptide ligandome presented by thymic epithelial cells

2023

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Within the thymus, thymic epithelial cells (TECs) provide a dedicated niche for the selection of functional T cells expressing a highly variable and self‐tolerant T‐cell receptor (TCR) repertoire. In this minireview, we start by summarizing recent studies that have improved our understanding on the composition of cortical TEC and medullary TEC microenvironments. Next, we focus on the molecular processes that control the function of TECs in T‐cell selection. In particular, we discuss the role of cortical TECs in positive selection and the pathways employed by these cells to generate and present selecting self‐peptides:MHC II complexes. Several studies have underscored the role of the β5t‐containing thymoproteasome in the production of unique MHC I‐bound peptides critical for CD8 T‐cell selection. Contrarily, the identity of the molecular determinants that regulate the generation of MHC II‐bound self‐peptides capable of positive selecting CD4 T cells is far more uncertain. We highlight recent advances that interconnect the autophagy‐lysosomal pathway, the presentation of specific sets of self‐peptide:MHC II complexes, and the diversification of CD4 TCR repertoire. Lastly, we discuss how these findings may open up new avenues for deciphering the identity of the MHC I and MHC II ligandome in the thymus.

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Aire suppresses CTLA-4 expression from the thymic stroma to control autoimmunity

Cited by 19 publications

References 60 publications

No Major Impact of Two Homologous Proteins Ly6C1 and Ly6C2 on Immune Homeostasis

No Major Impact of Two Homologous Proteins Ly6C1 and Ly6C2 on Immune Homeostasis

Development of organ‐specific autoimmunity by dysregulated Aire expression

T‐cell selection in the thymus: New routes toward the identification of the self‐peptide ligandome presented by thymic epithelial cells

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