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.