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 must 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 macrophage 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 contact with M-CSF-derived M phi exited the resting G0 state and re-entered the cell cycle, but experienced a sustained arrest near the first G1/S transition, followed by progressive apoptosis. In contrast, lymphocytes that were not stimulated remained viable, and could later activate normally when removed from contact with M phi. Functionally, exposure of T cells to alloantigens presented by M-CSF-derived M phi resulted in a selective depletion of the alloresponsive T cell population, while preserving reactivity to other mitogens and to alloantigens from different donors. The ability of M phi to impose activation-induced 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 IFN-gamma before differentiation. We speculate that this novel interaction may help to selectively delete autoreactive T cells that respond to self Ags presented by noninflammatory tissue M phi.
Munn
D H
DH
Division of Pediatric Hematology-Oncology, Medical College of Georgia, Augusta 30912, USA.
Pressey
J
J
Beall
A C
AC
Hudes
R
R
Alderson
M R
MR
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D015551:Autoimmunity / Q000502:physiology; D002453:Cell Cycle; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D017637:Clonal Deletion / Q000502:physiology*; D018920:Coculture Techniques; D016207:Cytokines / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008213:Lymphocyte Activation; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins / Q000494:pharmacology; D017634:Self Tolerance / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D019014:fas Receptor / Q000502:physiology
D000911:Antibodies, Monoclonal; D016207:Cytokines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D019014:fas Receptor; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma