ArticlePLoS genetics2012
A spontaneous mutation of the rat Themis gene leads to impaired function of regulatory T cells linked to inflammatory bowel disease.
Article in PLoS genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 38 citations in OpenAlex.
- The role of Themis in development of type 2 diabetes.Research square · 2025Article
- scRNA-seq reveals that VEGF signaling mediates the response to neoadjuvant anlotinib combined with PD-1 blockade therapy in non-small cell lung cancer.Journal of translational medicine · 2025Article
- A mutation in Themis contributes to anaphylaxis severity following oral peanut challenge in CC027 mice.The Journal of allergy and clinical immunology · 2024Article
- Positive regulation of Vav1 by Themis controls CD4 T cell pathogenicity in a mouse model of central nervous system inflammation.Cellular and molecular life sciences : CMLS · 2024Article
- Genetic haplotypes associated with immune response to Leishmania infantum infection in dogs.Veterinary research communications · 2023Article
- Themis suppresses the effector function of CD8Cellular & molecular immunology · 2023Article
- Flagellin-specific human CAR Tregs for immune regulation in IBD.Journal of autoimmunity · 2023Article
- Thymocyte regulatory variant alters transcription factor binding and protects from type 1 diabetes in infants.Scientific reports · 2022Article
- Negative times negative equals positive, THEMIS sets the rule on thymic selection and peripheral T cell responses.Biomedical journal · 2022Review
- A genome-wide circular RNA transcriptome in rat.Biology methods & protocols · 2021Article
- Rat models of human diseases and related phenotypes: a systematic inventory of the causative genes.Journal of biomedical science · 2020Review
- Rare coding variant analysis in a large cohort of Ashkenazi Jewish families with inflammatory bowel disease.Human genetics · 2018Article
- A simple twist of phosphate: Immunological synapse formation and T cell receptor signaling outcome in regulatory T cells.European journal of immunology · 2017Article
- An orthologous non-MHC locus in rats and mice is linked to CD4Genes and immunity · 2017Article
- Proteomic Analysis of Regulatory T Cells Reveals the Importance of Themis1 in the Control of Their Suppressive Function.Molecular & cellular proteomics : MCP · 2017Article
- Disrupted regulatory T cell homeostasis in inflammatory bowel diseases.World journal of gastroenterology · 2016Review
- Increased THEMIS First Exon Usage in CD4+ T-Cells Is Associated with a Genotype that Is Protective against Multiple Sclerosis.PloS one · 2016Article
- Genome-wide association study of recalcitrant atopic dermatitis in Korean children.The Journal of allergy and clinical immunology · 2015Article
- Therapeutic approaches for celiac disease.Best practice & research. Clinical gastroenterology · 2015Review
- Integrative biology of T cell activation.Nature immunology · 2014Review
Corrections and comments
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Authors and funding
16 authors at 7 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Spontaneous or chemically induced germline mutations, which lead to Mendelian phenotypes, are powerful tools to discover new genes and their functions. Here, we report an autosomal recessive mutation that occurred spontaneously in a Brown-Norway (BN) rat colony and was identified as causing marked T cell lymphopenia. This mutation was stabilized in a new rat strain, named BN(m) for "BN mutated." In BN(m) rats, we found that the T cell lymphopenia originated in the thymus, was intrinsic to CD4 T lymphocytes, and was associated with the development of an inflammatory bowel disease. Furthermore, we demonstrate that the suppressive activity of both peripheral and thymic CD4(+) CD25(bright) regulatory T cells (Treg) is defective in BN(m) rats. Complementation of mutant animals with BN Treg decreases disease incidence and severity, thus suggesting that the impaired Treg function is involved in the development of inflammatory bowel disease in BN(m) rats. Moreover, the cytokine profile of effector CD4 T cells is skewed toward Th2 and Th17 phenotypes in BN(m) rats. Linkage analysis and genetic dissection of the CD4 T cell lymphopenia in rats issued from BN(m)×DA crosses allowed the localization of the mutation on chromosome 1, within a 1.5 megabase interval. Gene expression and sequencing studies identified a frameshift mutation caused by a four-nucleotide insertion in the Themis gene, leading to its disruption. This result is the first to link Themis to the suppressive function of Treg and to suggest that, in Themis-deficient animals, defect of this function is involved in intestinal inflammation. Thus, this study highlights the importance of Themis as a new target gene that could participate in the pathogenesis of immune diseases characterized by chronic inflammation resulting from a defect in the Treg compartment.
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