TH1 CD4+ LYMPHOCYTES DELETE ACTIVATED MACROPHAGES THROUGH THE FAS APO-1 ANTIGEN PATHWAY/

The Fas/APO-1 cytotoxic pathway plays an important role in the regulat ion of peripheral immunity, Recent evidence indicates that this regula tory function operates through deletion of activated T and B lymphocyt es by CD4(+) T cells expressing the Fas ligand. Because macrophages pl ay a key role in peripheral immunity, we asked whether Fas was involve d in T-cell-macrophage interactions. Two-color flow cytometry revealed that Fas receptor (FasR) was expressed on resting murine peritoneal m acrophages, FasR expression was upregulated after activation of macrop hages with cytokines or lipopolysaccharide, although only tumor necros is factor-cc rendered macrophages sensitive to anti-FasR antibody-medi ated death. To determine the consequence of antigen presentation by ma crophages to CD4(+) T cells, macrophages were pulsed with antigen and then incubated with either Th1 or Th2 cell lines or clones. Th1, but n ot Th2, T cells induced lysis of 60-80% of normal macrophages, whereas macrophages obtained from mice with mutations in the FasR were totall y resistant to Th1-mediated cytotoxicity, Macrophage cytotoxicity depe nded upon specific antigen recognition by T cells and was major histoc ompatibility complex restricted. These findings indicate that, in addi tion to deletion of activated lymphocytes, Fas plays an important role in deletion of activated macrophages after antigen presentation to Th 1 CD4(+) T cells. Failure to delete macrophages that constitutively pr esent self-antigens may contribute to the expression of autoimmunity i n mice deficient in FasR (lpr) or Fas ligand (gld).