title: Genome-wide transcriptional analyses of islet-specific CD4+ T cells identify Idd9 genes controlling diabetogenic T cell function.
abstract: Type 1 diabetes (T1D) is a polygenic disease with multiple insulin-dependent diabetes (Idd) loci predisposing humans and NOD mice to disease. NOD.B10 Idd9 congenic mice, in which the NOD Idd9 chromosomal region is replaced by the Idd9 from T1D-resistant C57BL/10 mice, are significantly protected from T1D development. However, the genes and pathways conferring T1D development or protection by Idd9 remain to be fully elucidated. We have developed novel NOD.B10-Idd9 (line 905) congenic mice that predominantly harbor islet-reactive CD4(+) T cells expressing the BDC2.5 TCR (BDC-Idd9.905 mice). To establish functional links between the Idd9 genotype and its phenotype, we used microarray analyses to investigate the gene expression profiles of ex vivo and Ag-activated CD4(+) T cells from these mice and BDC2.5 (BDC) NOD controls. Among the differentially expressed genes, those located within the Idd9 region were greatly enriched in islet-specific CD4(+) T cells. Bioinformatics analyses of differentially expressed genes between BDC-Idd9.905 and BDC CD4(+) T cells identified Eno1, Rbbp4, and Mtor, all of which are encoded by Idd9 and part of gene networks involved in cellular growth and development. As predicted, proliferation and Th1/Th17 responses of islet-specific CD4(+) T cells from BDC-Idd9.905 mice following Ag stimulation in vitro were reduced compared with BDC mice. Furthermore, proliferative responses to endogenous autoantigen and diabetogenic function were impaired in BDC-Idd9.905 CD4(+) T cells. These findings suggest that differential expression of the identified Idd9 genes contributed to Idd9-dependent T1D susceptibility by controlling the diabetogenic function of islet-specific CD4(+) T cells.
authors: Department of Microbiology and Immunology, College of Medicine, Pennsylvania State University, Hershey, PA 17033;
authors: Gregory J
authors: GJ
authors: Berry
authors: Department of Microbiology and Immunology, College of Medicine, Pennsylvania State University, Hershey, PA 17033;
authors: Christine
authors: C
authors: Frielle
authors: Department of Microbiology and Immunology, College of Medicine, Pennsylvania State University, Hershey, PA 17033;
authors: Thaiphi
authors: T
authors: Luu
authors: Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA 17033; and.
authors: Anna C
authors: AC
authors: Salzberg
authors: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
authors: Daniel B
authors: DB
authors: Rainbow
authors: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
authors: Linda S
authors: LS
authors: Wicker
authors: Department of Microbiology and Immunology, College of Medicine, Pennsylvania State University, Hershey, PA 17033; huw10@psu.edu.
authors: Hanspeter
authors: H
authors: Waldner
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D049109:Cell Proliferation / Q000235:genetics; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics; D016000:Cluster Analysis; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D020869:Gene Expression Profiling / Q000379:methods*; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010751:Phosphopyruvate Hydratase / Q000235:genetics*; D056505:Retinoblastoma-Binding Protein 4 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D056505:Retinoblastoma-Binding Protein 4; D010751:Phosphopyruvate Hydratase