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J. Exp. Med., Volume 189, Number 2, January 18, 1999 347-358

The Role of Macrophages in T Cell-mediated Autoimmune Diabetes in Nonobese Diabetic Mice

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

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 Dagger  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 beta  cell-cytotoxic T cells, resulting in the prevention of autoimmune diabetes, but these T cells regained their beta  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 beta  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 beta  cell-cytotoxic T cells that cause beta  cell destruction, resulting in autoimmune diabetes in NOD mice.

Key words: macrophages;  T cells;  T cell activation;  nonobese diabetic mice;  autoimmune diabetes


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