Reduced CD4þ T-cell-specific gene expression in human type 1 diabetes mellitus Tihamer Orban a, * ,1 , Janos Kis a,b , Laszlo Szereday a,c , Peter Engelmann a,d , Klara Farkas a,e , Heyam Jalahej a , Andras Treszl a,f,1 a Section of Immunology and Immunogenetics, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02115, USA b Department of Internal Medicine and Gastroenterology, Polyclinic of the Hospitaller Brothers, Budapest 1027, Hungary c Reproductive and Tumor Immunology Research Group Hungarian Academy of Science, Pecs 7643, Hungary d Department of Immunology and Biotechnology, Faculty of Medicine, University of Pecs, Pecs 7643, Hungary e III Department of Medicine, Bajcsy-Zsilinszky Hospital, Budapest 1106, Hungary f First Department of Paediatrics, Semmelweis University, Budapest 1085, Hungary Received 30 March 2006; revised 4 January 2007; accepted 5 January 2007 Abstract 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 CD4þ T cells is altered in T1DM and analyzed unstimulated human peripheral blood CD4þ T-cell gene expression. We used a novel three-way comparison of DNA microarray data of CD4þ 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 glu- cose homeostasis on our findings. We analyzed the T1DM specific gene-expression changes and their functional relevance to T1DM autoim- munity. Our genetic and functional data show that T1DM CD4þ 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 CD4þ T cells showed impaired function, including an abnormal immune response, which may be a key element that leads to the breakdown of self-tolerance. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: Type 1 diabetes mellitus; CD4þ cells; DNA microarray 1. Introduction Type 1 diabetes mellitus (T1DM) in humans is character- ized by the T-cell-dependent destruction of the insulin produc- ing pancreatic beta cells. This view has been supported by the histopathologic finding of T cells in the insulitis of newly diagnosed patients with Type 1 diabetes [1]. Additional evidence is the selective beta cell destruction in a pancreas segment transplanted between discordant identical twins from a non-diabetic twin [2] and by the transfer of the disease following bone marrow transplantation from a diabetic donor to a non-diabetic immunocompromised recipient relative [3]. One of the significant limitations to studying the aetiopa- thogenesis of T1DM in humans is the inability to obtain tissue samples from the pancreatic lesions. Consequently, most of the data come from animal models of the disease, like the non- obese diabetic (NOD) mice [4]. In the NOD mouse both the CD4þ and CD8þ subsets of T lymphocytes act in concert in the development of the disease. The CD8þ cells play important roles in both the early and late Abbreviations: HDAC1, histone deacetylase 1. * Corresponding author. Tel.: þ1 617 713 3442; fax: þ1 617 732 2432. E-mail addresses: torban@joslin.harvard.edu (T. Orban), janos.kis@joslin. harvard.edu (J. Kis), laszlo.szereday@aok.pte.hu (L. Szereday), peter. engelmann@joslin.harvard.edu (P. Engelmann), klara.farkas@joslin.harvard. edu (K. Farkas), treszl@gyer1.sote.hu (A. Treszl). 1 These authors contributed equally to this work. 0896-8411/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.jaut.2007.01.002 Journal of Autoimmunity 28 (2007) 177e187 www.elsevier.com/locate/jautimm