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The Type 1 Diabetes Locus Idd6 Controls TLR1 Expression¹

David Vallois, Christina H. Grimm^2,*, Philip Avner^*, Christian Boitard and Ute Christine Rogner^3,*

^* Unité de Génétique Moléculaire Murine Centre National de la Recherche Scientifique, Unité de Recherche Associée 2578, Institut Pasteur, Paris, France; and Institut National de la Santé et de la Recherche Médicale Unité 561, Hôpital Cochin St. Vincent de Paul, Paris, France

The Idd6 locus on mouse chromosome 6, which controls the development of type 1 diabetes in the NOD mouse, affects proliferation rates of T cells and the activity of regulatory CD4⁺CD25⁺ T cells. Using a transcriptional profiling approach, we show that splenocytes and thymocytes from diabetes-resistant Idd6 NOD.C3H-congenic mouse strains exhibit a constitutive and specific down-regulation of Toll-like receptor 1 (Tlr1) gene expression compared with diabetes prone NOD mice. This phenotype correlates with a diminished proliferation capacity of both CD4⁺CD25^– effector and CD4⁺CD25⁺ regulatory T cells upon in vitro stimulation of the TLR1/TLR2 pathway by the ligand palmitoyl-3-cysteine-serine-lysine 4, and with the constitutive down-regulation of Tnf- and IL-6 in macrophages of Idd6- congenic mice. These data suggest that TLR1 is involved in the regulation of mechanisms that impinge on diabetes development in the NOD mouse.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Juvenile Diabetes Research Foundation International (1-2000-600), Agence National de la Recherche, and Association pour la Recherche sur le Diabète and recurrent funding from the Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, and Pasteur Institute.

² Current address: Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin, Germany.

³ Address correspondence and reprint requests to Dr. Ute C. Rogner, Génétique Moléculaire Murine Centre National de la Recherche Scientifique, Unité de Recherche Associée 2578, Institut Pasteur, 25 rue du Docteur Roux, Paris, France. E-mail address: urogner{at}pasteur.fr

⁴ Abbreviations used in this paper: T1D, type 1 diabetes; CO, control; h, human; Pam₃CSK₄, palmitoyl-3-cysteine-serine-lysine 4; PLN, pancreatic lymph node; Treg, regulatory T cell.

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