Similar Datasets
Project description:Insm1, encoding a zinc finger protein, is expressed specifically in neuroendocrine cells. Recent study showed the first evidence of Insm1 expression in medullary thymic epithelial cells (mTEC). Here we investigated the expression and function of Insm1 in mTEC. Mutation of Insm1 resulted in decreased proportion of mTEChi although normal development of other types of thymic cells. We detected altered expression of a subset of tissue-restricted antigens (TRAs) and mild decreased expression of Aire and Fezf2 in Insm1 mutant mTEC. We further showed that Insm1 recognizes a DNA sequence which is similar to the CCCTC-Binding factor (CTCF) binding motif. Mutation of Insm1 altered CTCF binding genome widely and thus the expression of genes. In nude mice transplanted with Insm1 mutant thymus, autoimmune responses were observed in multiple peripheral tissues. In thymus specific Insm1 mutant mice, we detected decreased induction of regulatory T (Treg) cells in the thymus, obvious lymphocytes infiltration and autoimmune antibody reaction in several peripheral tissues. In thymic epithelial cells specific Insm1 overexpression mice, we detected enlarged mTEC proportion and increased expression of mTEC specific genes. Thus, we suggest that Insm1 is a novel regulator of mTEC function and autoimmunity.
2024-01-01 | GSE193926 | GEO
Project description:Insm1, encoding a zinc finger protein, is expressed specifically in neuroendocrine cells. Recent study showed the first evidence of Insm1 expression in medullary thymic epithelial cells (mTEC). Here we investigated the expression and function of Insm1 in mTEC. Mutation of Insm1 resulted in decreased proportion of mTEChi although normal development of other types of thymic cells. We detected altered expression of a subset of tissue-restricted antigens (TRAs) and mild decreased expression of Aire and Fezf2 in Insm1 mutant mTEC. We further showed that Insm1 recognizes a DNA sequence which is similar to the CCCTC-Binding factor (CTCF) binding motif. Mutation of Insm1 altered CTCF binding genome widely and thus the expression of genes. In nude mice transplanted with Insm1 mutant thymus, autoimmune responses were observed in multiple peripheral tissues. In thymus specific Insm1 mutant mice, we detected decreased induction of regulatory T (Treg) cells in the thymus, obvious lymphocytes infiltration and autoimmune antibody reaction in several peripheral tissues. In thymic epithelial cells specific Insm1 overexpression mice, we detected enlarged mTEC proportion and increased expression of mTEC specific genes. Thus, we suggest that Insm1 is a novel regulator of mTEC function and autoimmunity.
2024-01-01 | GSE193927 | GEO
Project description:Insm1 regulates the expression of thymic tissue-restricted antigens and the immune tolerance
| PRJNA798413 | ENA
Project description:Insm1 regulates the expression of thymic tissue-restricted antigens and the immune tolerance [RNA-seq]
| PRJNA798415 | ENA
Project description:Insm1 regulates the expression of thymic tissue-restricted antigens and the immune tolerance [CUT&Tag]
| PRJNA798410 | ENA
Project description:Exosomes are nano-sized vesicles released by cells into the extracellular space and have been shown to be present in thymic tissue both in mice and in humans. The source of thymic exosomes is however still an enigma and hence it is not known whether thymic epithelial cells (TECs) are able to produce exosomes. In this work, we have cultured human TECs and isolated exosomes. These exosomes carry tissue-restricted antigens (TRAs), for example, myelin basic protein and desmoglein 3. The presence of TRAs indicates a possible role for thymic epithelium-derived exosomes in the selection process of thymocytes. The key contribution of these exosomes could be to disseminate self-antigens from the thymic epithelia, thus making them more accessible to the pool of maturing thymocytes. This would increase the coverage of TRAs within the thymus, and facilitate the process of positive and negative selection.
| S-EPMC4575951 | biostudies-literature
Project description:Positive and negative selection of thymocytes in the thymus are critical for the development of a mature and self-tolerant T-cell repertoire. The proapoptotic Bcl-2 family member Bim is important for negative selection by inducing apoptosis in thymocytes receiving a strong signal through their antigen receptor. However, in the case of ubiquitous self-antigens (UbA), Bim is not required for the clonal deletion of self-reactive thymocytes, suggesting the existence of nonapoptotic clonal deletion mechanisms. Unlike UbA, clonal deletion to tissue-restricted antigens (TRAs) requires positive selection and CCR7-mediated migration to the medulla. This led us to hypothesize that Bim is required for the latter. To study the role of Bim in clonal deletion to TRA, we constructed bone marrow (BM) chimeras using OT-I Bim-deficient or -sufficient donor bone marrow and recipients that express membrane bound chicken ovalbumin under control of the rat insulin promoter (Rip-mOVA). We found that clonal deletion to TRA was completely abrogated in the absence of Bim and large numbers of mature OT-I CD8 T cells survived in the periphery. Despite the large numbers of autoreactive T cells, the chimeras did not develop diabetes and OT-I Bim-deficient T cells from these chimeras were functionally impaired. Collectively, these data provide unique evidence of a differential, thymocyte-intrinsic, molecular requirement downstream of the T-cell receptor (TCR) for clonal deletion to UbA versus TRA and highlight the profound ability of other tolerance mechanisms to control T-cell autoreactivity in the absence of thymic clonal deletion.
| S-EPMC3271910 | biostudies-literature
Project description:To examine the Endocrine thymic epithelial cell transcriptome within the mTEC-III compartment we sorted this population from young Insm1 cKO mice and performed bulk RNAseq
2023-08-28 | GSE236073 | GEO
Project description:Central tolerance prevents autoimmunity, but also limits T cell responses to potentially immunodominant tumor epitopes with limited expression in healthy tissues. In peripheral APCs, γ-IFN-inducible lysosomal thiol reductase (GILT) is critical for MHC class II-restricted presentation of disulfide bond-containing proteins, including the self-antigen and melanoma Ag tyrosinase-related protein 1 (TRP1). The role of GILT in thymic Ag processing and generation of central tolerance has not been investigated. We found that GILT enhanced the negative selection of TRP1-specific thymocytes in mice. GILT expression was enriched in thymic APCs capable of mediating deletion, namely medullary thymic epithelial cells (mTECs) and dendritic cells, whereas TRP1 expression was restricted solely to mTECs. GILT facilitated MHC class II-restricted presentation of endogenous TRP1 by pooled thymic APCs. Using bone marrow chimeras, GILT expression in thymic epithelial cells (TECs), but not hematopoietic cells, was sufficient for complete deletion of TRP1-specific thymocytes. An increased frequency of TRP1-specific regulatory T (Treg) cells was present in chimeras with increased deletion of TRP1-specific thymocytes. Only chimeras that lacked GILT in both TECs and hematopoietic cells had a high conventional T/Treg cell ratio and were protected from melanoma challenge. Thus, GILT expression in thymic APCs, and mTECs in particular, preferentially facilitates MHC class II-restricted presentation, negative selection, and increased Treg cells, resulting in a diminished antitumor response to a tissue-restricted, melanoma-associated self-antigen.
| S-EPMC7336541 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-08-27 | GSE236075 | GEO