In¯ammatory 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 in¯ammatory lesion of non-obese diabetic mice or cloned islet-speci®c CD8 + T cells were ineffective in destroying islets on their own. Including increasing numbers of

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... phages 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, b 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-g production by CD8 + T cells. Each of these factors was partially effective, but not suf®cient, for maximal islet destruction. Antibodies speci®c 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.