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Hee-Sook Jun^*, Chang-Soon Yoon^*, Lori Zbytnuik^*, Nico van Rooijen, and Ji-Won Yoon^*,

From the ^* Julia McFarlane Diabetes Research Centre, Department of Microbiology and Infectious Diseases, Faculty of Medicine, The University of Calgary, Calgary, Alberta, Canada T2N 4N1; the Laboratory of Endocrinology, Institute for Medical Science, Department of Endocrinology and Metabolism, School of Medicine, Ajou University, Suwon, Korea 442-749; and the Department of Cell Biology & Immunology, Faculty of Medicine, Free University, Amsterdam, The Netherlands 1081 BT

We have shown previously that the inactivation of macrophages in nonobese diabetic (NOD) mice results in the prevention of diabetes; however, the mechanisms involved remain unknown. In this study, we found that T cells in a macrophage-depleted environment lost their ability to differentiate into β cell–cytotoxic T cells, resulting in the prevention of autoimmune diabetes, but these T cells regained their β cell–cytotoxic potential when returned to a macrophage-containing environment. To learn why T cells in a macrophage-depleted environment lose their ability to kill β cells, we examined the islet antigen–specific immune response and T cell activation in macrophage-depleted NOD mice. There was a shift in the immune balance, a decrease in the T helper cell type 1 (Th1) immune response, and an increase in the Th2 immune response, due to the reduced expression of the macrophage-derived cytokine IL-12. As well, there was a deficit in T cell activation, evidenced by significant decreases in the expression of Fas ligand and perforin. The administration of IL-12 substantially reversed the prevention of diabetes in NOD mice conferred by macrophage depletion. We conclude that macrophages play an essential role in the development and activation of β cell–cytotoxic T cells that cause β cell destruction, resulting in autoimmune diabetes in NOD mice.

Key Words: macrophages • T cells • T cell activation • nonobese diabetic mice • autoimmune diabetes

The authors gratefully acknowledge the excellent technical assistance of Ms. L. Bryant for FACS^® analyses and the editorial assistance of Ms. Karen Clarke and Dr. A.L. Kyle.

Abbreviations used: BB, BioBreeding; CY, cyclophosphamide; FasL, Fas ligand; GAD, glutamic acid decarboxylase; HPRT, hypoxanthine phosphoribosyl transferase; lip-Cl₂MDP, liposomal dichloromethylene diphosphonate; NOD, nonobese diabetic.

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