A Spontaneous Mutation of the Rat Gene Leads to Impaired Function of Regulatory T Cells Linked to Inflammatory Bowel Disease
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 BNm for “BN mutated.” In BNm 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+ CD25bright regulatory T cells (Treg) is defective in BNm 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 BNm rats. Moreover, the cytokine profile of effector CD4 T cells is skewed toward Th2 and Th17 phenotypes in BNm rats. Linkage analysis and genetic dissection of the CD4 T cell lymphopenia in rats issued from BNm×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.
Vyšlo v časopise:
A Spontaneous Mutation of the Rat Gene Leads to Impaired Function of Regulatory T Cells Linked to Inflammatory Bowel Disease. PLoS Genet 8(1): e32767. doi:10.1371/journal.pgen.1002461
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002461
Souhrn
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 BNm for “BN mutated.” In BNm 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+ CD25bright regulatory T cells (Treg) is defective in BNm 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 BNm rats. Moreover, the cytokine profile of effector CD4 T cells is skewed toward Th2 and Th17 phenotypes in BNm rats. Linkage analysis and genetic dissection of the CD4 T cell lymphopenia in rats issued from BNm×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.
Zdroje
1. HunterDJ 2005 Gene-environment interactions in human diseases. Nat Rev Genet 6 287 298
2. XavierRJRiouxJD 2008 Genome-wide association studies: a new window into immune-mediated diseases. Nat Rev Immunol 8 631 643
3. BaranziniSE 2009 The genetics of autoimmune diseases: a networked perspective. Curr Opin Immunol 21 596 605
4. SawcerSHellenthalGPirinenMSpencerCCPatsopoulosNA 2011 Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476 214 219
5. DavissonMT 2005 Discovery genetics: serendipity in basic research. ILAR J 46 338 345
6. Acevedo-ArozenaAWellsSPotterPKellyMCoxRD 2008 ENU mutagenesis, a way forward to understand gene function. Annu Rev Genomics Hum Genet 9 49 69
7. IzcueACoombesJLPowrieF 2009 Regulatory lymphocytes and intestinal inflammation. Annu Rev Immunol 27 313 338
8. FuGValleeSRybakinVMcGuireMVAmpudiaJ 2009 Themis controls thymocyte selection through regulation of T cell antigen receptor-mediated signaling. Nat Immunol 10 848 856
9. JohnsonALAravindLShulzhenkoNMorgunAChoiSY 2009 Themis is a member of a new metazoan gene family and is required for the completion of thymocyte positive selection. Nat Immunol 10 831 839
10. LesourneRUeharaSLeeJSongKDLiL 2009 Themis, a T cell-specific protein important for late thymocyte development. Nat Immunol 10 840 847
11. PatrickMSOdaHHayakawaKSatoYEshimaK 2009 Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes. Proc Natl Acad Sci U S A 106 16345 16350
12. KoseHSakaiTTsukumoSWeiKYamadaT 2007 Maturational arrest of thymocyte development is caused by a deletion in the receptor-like protein tyrosine phosphatase kappa gene in LEC rats. Genomics 89 673 677
13. BrockmeyerCPasterWPepperDTanCPTrudgianDC 2011 T cell receptor (TCR)-induced tyrosine phosphorylation dynamics identifies THEMIS as a new TCR signalosome component. J Biol Chem 286 7535 7547
14. AguiTOkaMYamadaTSakaiTIzumiK 1990 Maturational arrest from CD4+8+ to CD4+8− thymocytes in a mutant strain (LEC) of rat. J Exp Med 172 1615 1624
15. AsanoATsubomatsuKJungCGSasakiNAguiT 2007 A deletion mutation of the protein tyrosine phosphatase kappa (Ptprk) gene is responsible for T-helper immunodeficiency (thid) in the LEC rat. Mamm Genome 18 779 786
16. IwataRSasakiNAguiT 2010 Contiguous gene deletion of Ptprk and Themis causes T-helper immunodeficiency (thid) in the LEC rat. Biomed Res 31 83 87
17. FuGChenYYuMPoddASchumanJ 2010 Phospholipase C{gamma}1 is essential for T cell development, activation, and tolerance. J Exp Med 207 309 318
18. KoonpaewSShenSFlowersLZhangW 2006 LAT-mediated signaling in CD4+CD25+ regulatory T cell development. J Exp Med 203 119 129
19. SommersCLLeeJSteinerKLGursonJMDepersisCL 2005 Mutation of the phospholipase C-gamma1-binding site of LAT affects both positive and negative thymocyte selection. J Exp Med 201 1125 1134
20. ChuckMIZhuMShenSZhangW 2010 The role of the LAT-PLC-gamma1 interaction in T regulatory cell function. J Immunol 184 2476 2486
21. ChoJH 2008 The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol 8 458 466
22. AbrahamCChoJH 2009 Inflammatory bowel disease. N Engl J Med 361 2066 2078
23. MarksDJHarbordMWMacAllisterRRahmanFZYoungJ 2006 Defective acute inflammation in Crohn's disease: a clinical investigation. Lancet 367 668 678
24. PodolskyDK 2002 Inflammatory bowel disease. N Engl J Med 347 417 429
25. BarrettJCHansoulSNicolaeDLChoJHDuerrRH 2008 Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 40 955 962
26. FrankeAMcGovernDPBarrettJCWangKRadford-SmithGL 2010 Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 42 1118 1125
27. DuboisPCTrynkaGFrankeLHuntKARomanosJ 2010 Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42 295 302
28. FestenEASzperlAMWeersmaRKWijmengaCWapenaarMC 2009 Inflammatory bowel disease and celiac disease: overlaps in the pathology and genetics, and their potential drug targets. Endocr Metab Immune Disord Drug Targets 9 199 218
29. CasellaGD'IncaROlivaLDapernoMSaladinoV 2010 Prevalence of celiac disease in inflammatory bowel diseases: An IG-IBD multicentre study. Dig Liver Dis 42 175 178
30. TursiAGiorgettiGMBrandimarteGEliseiW 2005 High prevalence of celiac disease among patients affected by Crohn's disease. Inflamm Bowel Dis 11 662 666
31. FestenEAGoyettePGreenTBoucherGBeauchampC 2011 A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease. PLoS Genet 7 e1001283 doi:10.1371/journal.pgen.1001283
32. LettreGRiouxJD 2008 Autoimmune diseases: insights from genome-wide association studies. Hum Mol Genet 17 R116 121
33. CavaillesPSergentVBisanzCPapapietroOColaciosC 2006 The rat Toxo1 locus directs toxoplasmosis outcome and controls parasite proliferation and spreading by macrophage-dependent mechanisms. Proc Natl Acad Sci U S A 103 744 749
34. BromanKWWuHSenSChurchillGA 2003 R/qtl: QTL mapping in experimental crosses. Bioinformatics 19 889 890
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2012 Číslo 1
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Poly(ADP-Ribose) Polymerase 1 (PARP-1) Regulates Ribosomal Biogenesis in Nucleoli
- Microenvironmental Regulation by Fibrillin-1
- Parallel Mapping and Simultaneous Sequencing Reveals Deletions in and Associated with Discrete Inherited Disorders in a Domestic Dog Breed
- Two-Component Elements Mediate Interactions between Cytokinin and Salicylic Acid in Plant Immunity