The role of macrophages in T cell-mediated autoimmune diabetes in nonobese diabetic mice.
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.
Jun
H S
HS
Julia McFarlane Diabetes Research Centre, Department of Microbiology and Infectious Diseases, Faculty of Medicine, The University of Calgary, Calgary, Alberta, Canada T2N 4N1.
Yoon
C S
CS
Zbytnuik
L
L
van Rooijen
N
N
Yoon
J W
JW
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D004002:Clodronic Acid / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003920:Diabetes Mellitus / Q000235:genetics / Q000276:immunology; D053222:Fas Ligand Protein; D005260:Female; D018664:Interleukin-12 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000187:drug effects / Q000473:pathology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D016378:Tissue Transplantation
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D004002:Clodronic Acid; D054353:Perforin; D018664:Interleukin-12