The role of macrophages in T cell-mediated autoimmune diabetes in nonobese diabetic mice

• Published in: The Journal of experimental medicine Vol. 189; no. 2; pp. 347 - 358
• Main Authors: Jun, H S, Yoon, C S, Zbytnuik, L, van Rooijen, N, Yoon, J W
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 18.01.1999
• Subjects: Animals; Autoimmunity - immunology; Cell Differentiation - immunology; Clodronic Acid - pharmacology; Cytotoxicity, Immunologic - immunology; Diabetes Mellitus - genetics; Diabetes Mellitus - immunology; Fas Ligand Protein; Female; Interleukin-12 - pharmacology; Islets of Langerhans - drug effects; Islets of Langerhans - immunology; Macrophages - immunology; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred NOD; Pancreas - drug effects; Pancreas - pathology; Perforin; Pore Forming Cytotoxic Proteins; Spleen - immunology; T-Lymphocytes - immunology; Tissue Transplantation
• DOI: 10.1084/jem.189.2.347
• ISSN: 0022-1007

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.