Antigen-independent cross-talk between macrophages and CD8+ T cells facilitates their cooperation during target destruction.
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, beta 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-gamma 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.
Gurlo
Tatyana
T
Division of Endocrinology and Diabetes, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
von Grafenstein
Hermann
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D017951:Antigen Presentation; D001402:B-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic; D005260:Female; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007515:Islets of Langerhans / Q000166:cytology / Q000276:immunology*; D008213:Lymphocyte Activation; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008858:Microscopy, Phase-Contrast; D009569:Nitric Oxide / Q000096:biosynthesis
D000911:Antibodies, Monoclonal; D009569:Nitric Oxide; D007371:Interferon-gamma