Reduced CD4+ T-cell-specific gene expression in human type 1 diabetes mellitus.
Type 1 diabetes mellitus (T1DM) in humans is characterized by the T-cell-dependent destruction of the insulin producing pancreatic beta cells; however, the precise pathogenesis of the disease, especially the initiation of pathologic immune response, is still largely unknown. We hypothesized that the function of human CD4+ T cells is altered in T1DM and analyzed unstimulated human peripheral blood CD4+ T-cell gene expression. We used a novel three-way comparison of DNA microarray data of CD4+ T cells isolated from patients with new onset T1DM, patients with long-term Type 2 diabetes (T2DM), and from healthy control subjects in order to eliminate any possible influence of glucose homeostasis on our findings. We analyzed the T1DM specific gene-expression changes and their functional relevance to T1DM autoimmunity. Our genetic and functional data show that T1DM CD4+ T cells are down-regulated specifically affecting key immune functions and cell cycle. Histone deacetylase gene expression, a key regulator of epigenetic modification is also reduced. The CD4+ T cells showed impaired function, including an abnormal immune response, which may be a key element that leads to the breakdown of self-tolerance.
Orban
Tihamer
T
Section of Immunology and Immunogenetics, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02115, USA. torban@joslin.harvard.edu
Kis
Janos
J
Szereday
Laszlo
L
Engelmann
Peter
P
Farkas
Klara
K
Jalahej
Heyam
H
Treszl
Andras
A
D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015536:Down-Regulation / Q000276:immunology; D044127:Epigenesis, Genetic / Q000276:immunology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008297:Male
D006655:Histone Deacetylases