HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Havari, E. Articles by Lipes, M. A. Search for Related Content PubMed PubMed Citation Articles by Havari, E. Articles by Lipes, M. A.

Expression of the B7.1 Costimulatory Molecule on Pancreatic Cells Abrogates the Requirement for CD4 T Cells in the Development of Type 1 Diabetes¹

Evis Havari^*, Ana Maria Lennon-Dumenil, Ludger Klein, Devon Neely^*, Jacqueline A. Taylor^*, Marcia F. McInerney^*, Kai W. Wucherpfennig and Myra A. Lipes^2,*

^* Joslin Diabetes Center, Boston, MA 02215, and Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Department of Pathology, Harvard Medical School, Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, and Department of Neurology, Harvard Medical School, Boston, MA 02115

Although HLA-DQ8 has been implicated as a key determinant of genetic susceptibility to human type 1 diabetes, spontaneous diabetes has been observed in HLA-DQ8 transgenic mice that lack expression of murine MHC class II molecules (mII^–/–) only when the potent costimulatory molecule, B7.1, is transgenically expressed on pancreatic cells. To study the contribution of HLA-DQ8 to the development of diabetes in this model, we crossed RIP-B7.1mII^–/– mice with a set of transgenic mouse lines that differed in their HLA-DQ8 expression patterns on APC subpopulations, in particular dendritic cells and cortical thymic epithelial cells. Surprisingly, we found that even in the absence of HLA-DQ8 and CD4 T cells, a substantial fraction of the RIP-B7.1mII^–/– mice developed diabetes. This disease process was remarkable for not only showing insulitis, but also inflammatory destruction of the exocrine pancreas with diffusely up-regulated expression of MHC class I and ICAM-1 molecules. Expression of HLA-DQ8 markedly increased the kinetics and frequency of diabetes, with the most severe disease in the lines with the highest levels of HLA-DQ8 on cortical thymic epithelial cells and the largest numbers of CD4 T cells. However, the adoptive transfer of diabetes was not HLA-DQ8-dependent and disease could be rapidly induced with purified CD8 T cells alone. Expression of B7.1 in the target tissue can thus dramatically alter the cellular and molecular requirements for the development of autoimmunity.

This article has been cited by other articles:

				A. Ueno, S. Cho, L. Cheng, Z. Wang, B. Wang, and Y. Yang Diabetes Resistance/Susceptibility in T Cells of Nonobese Diabetic Mice Conferred by MHC and MHC-Linked Genes J. Immunol., October 15, 2005; 175(8): 5240 - 5247. [Abstract] [Full Text] [PDF]

				F. S. Wong, W. Du, I. J. Thomas, and L. Wen The Influence of the Major Histocompatibility Complex on Development of Autoimmune Diabetes in RIP-B7.1 Mice Diabetes, July 1, 2005; 54(7): 2032 - 2040. [Abstract] [Full Text] [PDF]