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The thymus is a highly specialized organ that plays an indispensable role in the establishment of self-tolerance, a process characterized by the “education” of developing T-cells. To provide competent T-cells tolerant to self-antigens, medullary thymic epithelial cells (mTECs) orchestrate negative selection by ectopically expressing a wide range of genes, including various tissue-restricted antigens (TRAs). Notably, recent advancements in the high-throughput single-cell analysis have revealed remarkable heterogeneity in mTECs, giving us important clues for dissecting the mechanisms underlying TRA expression. We overview how recent single-cell studies have furthered our understanding of mTECs, with a focus on the role of Aire in inducing mTEC heterogeneity to encompass TRAs.

Thymocyte trafficking has an important role in thymic selection. Here we show that the Hippo homologue Mst1 is required for thymocyte migration and antigen recognition by LFA-1 and ICAM-1 within the medulla. Using two-photon imaging of thymic tissues, we found that highly motile mature thymocytes arrest and are activated in the vicinity of rare populations of Aire + ICAM-1 hi medullary thymic epithelia in a negatively selecting environment. Notably, Mst1 deficiency or blocking the cell adhesion molecules LFA-1 and ICAM-1 results in inefficient migration and antigen recognition of CD4 + thymocytes within the medulla. Consistent with these defects, thymocyte selection is impaired in Mst1 −/− mice, which display T cell-dependent inflammatory infiltrates in multiple organs and develop autoantibodies. Our results suggest that Mst1 has a key role in regulating thymocyte self-antigen recognition in the medulla. Autoreactive T cells are eliminated as they encounter self-antigens during transit through the thymus. Ueda et al . reveal that mice lacking the Hippo homologue Mst1 develop autoimmunity as a result of impaired integrin-dependent T cell migration through this negatively selective niche.

The autoimmune regulator Aire is expressed in a small proportion of medullary thymic epithelial cells (mTECs) and is crucial in the induction of central T cell tolerance. The origin and development of Aire + mTECs, however, are not well understood. Here we demonstrate that the tight-junction components claudin-3 and claudin-4 (Cld3,4) were 'preferentially' expressed in Aire + mTECs. In early ontogeny, Cld3,4 hi TECs derived from the most apical layer of the stratified thymic anlage first expressed known mTEC markers such as UEA-1 ligand and MTS10. We provide evidence that such Cld3,4 hi UEA-1 + TECs represented the initial progenitors specified for Aire + mTECs, whose development crucially required NF-κB-inducing kinase and the adaptor molecule TRAF6. Our results suggest that Aire + mTECs represent terminally differentiated cells in a unique lineage arising during thymic organogenesis.

The microenvironments of the thymus are generated by thymic epithelial cells (TECs) and are essential for inducing immune self-tolerance or developing T cells. However, the molecular mechanisms that underlie the differentiation of TECs and thymic compartmentalization are not fully understood. Here we show that deficiency in the tumor necrosis factor receptor-associated factor (TRAF) 6 results in disorganized distribution of medullary TECs (mTECs) and the absence of mature mTECs. Engraftment of thymic stroma of TRAF6[superscript -/-] embryos into athymic nude mice induced autoimmunity. Thus, TRAF6 directs the development of thymic stroma and represents a critical point of regulation for self-tolerance and autoimmunity.

Despite the clear distinction between cortical (cTECs) and medullary thymic epithelial cells (mTECs) in physiology, the cell of origin of thymic carcinomas (TCs) and other thymic epithelial tumors remained enigmatic. We addressed this issue by focusing on AIRE, an mTEC‐specific transcriptional regulator that is required for immunological self‐tolerance. We found that a large proportion of TCs expressed AIRE with typical nuclear dot morphology by immunohistochemistry. AIRE expression in TCs was supported by the RNA‐seq data in the TCGA‐THYM database. Furthermore, our bioinformatics approach to the recent single‐cell RNA‐seq data on human thymi has revealed that TCs hold molecular characteristics of multiple mTEC subpopulations. In contrast, TCs lacked the gene signatures for cTECs. We propose that TCs are tumors derived from mTECs. Thymic epithelial tumors originating from thymic epithelial cells (TECs) are classified into six types of thymomas (Type A, AB, B1‐B3 thymomas, and micronodular thymoma with lymphoid stroma [MNT]) and thymic carcinoma (TC). Despite the clear distinction between cortical (cTECs) and medullary TECs (mTECs) in physiology, the cell of origin of each TET has remained enigmatic. In the current study, we confirmed the expression of AIRE, an mTEC‐specific transcriptional regulator, in most TCs at both protein and mRNA levels. Furthermore, our bioinformatics approach has revealed that TCs hold molecular characteristics of multiple mTEC subpopulations, suggesting their cell of origin as mTECs.

The discovery of Aire-dependent transcriptional control of many tissue-restricted self-antigen (TRA) genes in thymic epithelial cells in the medulla (medullary thymic epithelial cells, mTECs) has raised the intriguing question of how the single Aire gene can influence the transcription of such a large number of TRA genes within mTECs. From a mechanistic viewpoint, there are two possible models to explain the function of Aire in this action. In the first model, TRAs are considered to be the direct target genes of Aire's transcriptional activity. In this scenario, the lack of Aire protein within cells would result in the defective TRA gene expression, while the maturation program of mTECs would be unaffected in principle. The second model hypothesizes that Aire is necessary for the maturation program of mTECs. In this case, we assume that the mTEC compartment does not mature normally in the absence of Aire. If acquisition of the properties of TRA gene expression depends on the maturation status of mTECs, a defect of such an Aire-dependent maturation program in Aire-deficient mTECs can also result in impaired TRA gene expression. In this brief review, we will focus on these two contrasting models for the roles of Aire in controlling the expression of TRAs within mTECs.

Thymic epithelial cells (TECs) play pivotal roles in the establishment of self tolerance through critical dialogue with developing thymocytes. Unique actions of two transcriptional regulators within TECs, NF-κB-inducing kinase (NIK) and an autoimmune regulator (AIRE), for the establishment of self tolerance have recently been highlighted by studies using a strain of mouse bearing a natural mutation of the NIK gene (aly mice) and gene-targeted mice, respectively. Previous studies have demonstrated essential roles of NIK downstream of the lymphotoxin-β receptor (LTβR), which is essential for the development of secondary lymphoid organs; aly mice lack all lymph nodes and Peyer's patches because of the defective LTβR signaling. Additional roles of NIK in thymic organogenesis downstream of LTβR, mainly through the developmental regulation of TECs, have now emerged, although the corresponding ligand(s) for LTβR participating in this action have not been fully characterized. In contrast, AIRE, a gene responsible for the development of an organ-specific autoimmune disease that demonstrates monogenic autosomal recessive inheritance, contributes to the establishment of self tolerance probably by controlling the expression of self antigens through yet undetermined molecular mechanisms. Thus, it is highly likely that a group of genes control self tolerance within TECs through unique and coordinated actions, and that an understanding of this process would help to unravel the pathogenesis of autoimmune disease.

There are seven Vγ gene segments in the TCR γ chain loci of mice. We developed monoclonal antibodies (mAbs) specific to the Vγ6 chain (Heilig & Tonegawa nomenclature). By immunizing Vγ4/6 KO mice with complementarity-determining region peptides in Vγ6 chains, we generated three hybridomas. These hybridomas produced mAbs capable of cell surface staining of Vγ6/Vδ1 gene–transfected T-cell line lacking TCR as well as of Vγ1 − Vγ4 − Vγ5 − Vγ7 − γδ T cells and the CD3 high TCRδ int γδ T cells in various organs. The location of Vγ6 + γδ T cells, which peaked in the newborn thymus, was associated with mTEC. In vivo administration of clone 1C10-1F7 mAb impaired protection against Klebsiella pneumoniae infection but ameliorated psoriasis-like dermatitis induced by imiquimod treatment. These new mAbs are useful to elucidate the development, location, and functions of Vγ6 γδ T cells in mice.

Controlled proteolytic degradation of specialized junctional structures, corneodesmosomes, by epidermal proteases is an essential process for physiological desquamation of the skin. Corneodesmosin (CDSN) is an extracellular component of corneodesmosomes and, although considerable debate still exists, genetic studies have suggested that the CDSN gene in the major psoriasis-susceptibility locus (PSORS1) may be responsible for susceptibility to psoriasis, a human skin disorder characterized by excessive growth and aberrant differentiation of keratinocytes. CDSN is also expressed in the inner root sheath of hair follicles, and a heterozygous nonsense mutation of the CDSN gene in humans is associated with scalp-specific hair loss of poorly defined etiology. Here, we have investigated the pathogenetic roles of CDSN loss of function in the development of skin diseases by generating a mouse strain with targeted deletion of the Cdsn gene. Cdsn-deficient mouse skin showed detachment of the stratum corneum from the underlying granular layer and/or detachment within the upper granular layers due to the disrupted integrity of the corneodesmosomes. When grafted onto immunodeficient mice, Cdsn-deficient skin showed rapid hair loss together with epidermal abnormalities resembling psoriasis. These results underscore the essential roles of CDSN in hair physiology and suggest functional relevance of CDSN gene polymorphisms to psoriasis susceptibility.

Mutation of the autoimmune regulator (AIRE) gene is responsible for the development of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), an organ-specific autoimmune disease with monogenic autosomal recessive inheritance. AIRE is strongly expressed in thymic epithelial cells (TECs), and its structural features suggest that it probably acts as a transcriptional regulator. The role of Aire in the elimination of autoreactive T cells (i.e., negative selection) has been well demonstrated with the use of transgenic mouse models, although how Aire regulates this process in TECs has yet to be determined. Aire also regulates other features of autoimmunity, such as target-organ specificity of autoimmune destruction, suggesting that an understanding of the relationship between AIRE gene malfunction and the breakdown of self-tolerance promises to help unravel the pathogenesis of not only APECED but also other types of autoimmune diseases. Owing to this unique tolerogenic function of Aire, the cellular origin and developmental process of Aire-expressing TECs is now becoming an interesting field for intense research.