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

doi:10.1084/jem.189.2.347

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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^*

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 ofdiabetes; however, the mechanisms involved remain unknown. Inthis study, we found that T cells in a macrophage-depleted environmentlost their ability to differentiate into $beta$ cell-cytotoxic T cells,resulting in the prevention of autoimmune diabetes, but theseT cells regained their $beta$ cell-cytotoxic potential when returnedto a macrophage-containing environment. To learn why T cells ina macrophage-depleted environment lose their ability to kill $beta$ cells, we examined the islet antigen-specific immune responseand T cell activation in macrophage-depleted NOD mice. There wasa shift in the immune balance, a decrease in the T helper celltype 1 (Th1) immune response, and an increase in the Th2 immuneresponse, due to the reduced expression of the macrophage-derivedcytokine IL-12. As well, there was a deficit in T cell activation,evidenced by significant decreases in the expression of Fas ligandand perforin. The administration of IL-12 substantially reversedthe prevention of diabetes in NOD mice conferred by macrophagedepletion. We conclude that macrophages play an essential rolein the development and activation of $beta$ cell-cytotoxic T cellsthat cause $beta$ cell destruction, resulting in autoimmune diabetesin NODmice.

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

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