SELECTIVE ACTIVATION-INDUCED APOPTOSIS OF PERIPHERAL T-CELLS IMPOSED BY MACROPHAGES - A POTENTIAL MECHANISM OF ANTIGEN-SPECIFIC PERIPHERAL LYMPHOCYTE DELETION

The self-reactive T cells that escape clonal deletion in the thymus mu st be suppressed by the less well characterized process of peripheral tolerance, In this study, we show that monocyte-derived macrophages (M phi) undergoing terminal differentiation in the presence of macrophag e CSF (M-CSF) acquire the ability to selectively induce apoptosis of T cells in an activation-specific fashion, Lymphocytes were stimulated via the TCR using anti-CD3 cross-linking, staphylococcal superantigen, or allogeneic mixed-leukocyte cultures, T cells activated while in co ntact with M-CSF-derived M phi exited the resting G(0) state and re-en tered the cell cycle, but experienced a sustained arrest near the firs t G(1)/S transition, followed by progressive apoptosis, In contrast, l ymphocytes that were not stimulated remained viable, and could later a ctivate normally when removed from contact with M phi. Functionally, e xposure of T cells to alloantigens presented by M-CSF-derived M phi re sulted in a selective depletion of the alloresponsive T cell populatio n, while preserving reactivity to other mitogens and to alloantigens f rom different donors, The ability of M phi to impose activation-induce d apoptosis on lymphocytes was regulated developmentally, being absent in fresh monocytes, progressively acquired during differentiation in M-CSF, and abrogated if monocytes were exposed to lFN-gamma before dif ferentiation, We speculate that this novel interaction may help to sel ectively delete autoreactive T cells that respond to self Ags presente d by noninflammatory tissue M phi.