International Immunology, Vol. 15, No. 9, pp. 1063-1071,
September 2003
© 2003 Japanese Society for Immunology
Antigen-independent cross-talk between macrophages and CD8+ T cells facilitates their cooperation during target destruction
1 Division of Endocrinology and Diabetes, Department of Medicine, Keck School of Medicine,University of Southern California, Los Angeles, CA 90033, USA 2 Departments of Medicinal & Biological Chemistry and Pharmacology, College of Pharmacy,University of Toledo, Toledo, OH 43606, USA
Correspondence to: H. von Grafenstein, Department of Medicinal & Biological Chemistry, College of Pharmacy, University of Toledo,2801 West Bancroft Street, MS #606, Toledo, OH 43606, USA. E-mail: hgrafen{at}utnet.utoledo.edu
Transmitting editor: T. Watanabe
Inflammatory sites associated with tissue destruction often contain a complex mixture of cells including macrophages as well as CD8+ and CD4+ T cells. Here, we have investigated, using islets of Langerhans as targets, if CD8+ T cells and macrophages can cooperate in tissue destruction. CD8+ T cells obtained from the islet inflammatory lesion of non-obese diabetic mice or cloned islet-specific CD8+ T cells were ineffective in destroying islets on their own. Including increasing numbers of macrophages in co-cultures of islets and islet-derived or cloned CD8+ T cells progressively increased and accelerated islet destruction. Macrophages alone were ineffective. Macrophage-depleted islets were not destroyed by islet-derived CD8+ T cells. For cooperative islet destruction to occur, ß cells, but not macrophages, needed to be able to present antigens to CD8+ T cells. CD8+ T cells triggered NO production by macrophages, while macrophages triggered IFN-
production by CD8+ T cells. Each of these factors was partially effective, but not sufficient, for maximal islet destruction. Antibodies specific for ICAM-1 and LFA-1 inhibited both cooperative islet destruction and cross-stimulation of CD8+ T cells and macrophages. The data suggest that if CD8+ T cells become only weakly activated by target cells, they are not able to destroy target tissue on their own. However, such CD8+ T cells and local macrophages may still cross-stimulate each other, which then facilitates target destruction. For this to occur, target cells, but not macrophages, need to present antigen to CD8+ T cells.
Keywords: cell–cell interaction, ICAM-1, LFA-1, NO, type 1 diabetes
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