title: Development of type 1 diabetes mellitus in nonobese diabetic mice follows changes in thymocyte and peripheral T lymphocyte transcriptional activity.
abstract: As early as one month of age, nonobese diabetic (NOD) mice feature pancreatic infiltration of autoreactive T lymphocytes, which destruct insulin-producing beta cells, producing autoimmune diabetes mellitus (T1D) within eight months. Thus, we hypothesized that during the development of T1D, the transcriptional modulation of immune reactivity genes may occur as thymocytes mature into peripheral T lymphocytes. The transcriptome of thymocytes and peripheral CD3⁺ T lymphocytes from prediabetic or diabetic mice analyzed through microarray hybridizations identified 2,771 differentially expressed genes. Hierarchical clustering grouped mice according to age/T1D onset and genes according to their transcription profiling. The transcriptional activity of thymocytes developing into peripheral T lymphocytes revealed sequential participation of genes involved with CD4⁺/CD8⁺ T-cell differentiation (Themis), tolerance induction by Tregs (Foxp3), and apoptosis (Fasl) soon after T-cell activation (IL4), while the emergence of T1D coincided with the expression of cytotoxicity (Crtam) and inflammatory response genes (Tlr) by peripheral T lymphocytes.
authors.affiliation: Molecular Immunogenetics Group, Department of Genetics, Faculty of Medicine of Ribeirão Preto, University of São Paulo (USP), 14040-900 School Ribeirão Preto, SP, Brazil.
authors.forename: Thais A
authors.initials: TA
authors.lastname: Fornari
authors.forename: Paula B
authors.initials: PB
authors.lastname: Donate
authors.forename: Claudia
authors.initials: C
authors.lastname: Macedo
authors.forename: Elza T
authors.initials: ET
authors.lastname: Sakamoto-Hojo
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Donadi
authors.forename: Geraldo A
authors.initials: GA
authors.lastname: Passos
mesh_terms: D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods*; D055106:Genome-Wide Association Study / Q000379:methods*; D023281:Genomics / Q000379:methods*; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D015847:Interleukin-4 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: C491899:Fas protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007136:Immunoglobulins; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D051193:Toll-Like Receptors; C408522:class-I restricted T cell-associated molecule; D019014:fas Receptor; C544192:themis protein, mouse; D015847:Interleukin-4