CD95 (APO-1 FAS)-MEDIATED APOPTOSIS IN CYTOKINE-ACTIVATED HEMATOPOIETIC-CELLS/

Elimination of peripheral T cells is crucially regulated via apoptosis through CD95 (APO-1/Fas) receptor ligand interaction. Because homeost asis in hematopoietic cells may also involve the CD95 system, we analy zed CD95 expression and sensitivity to CD95-induced apoptosis in human bone marrow cells. During hematopoiesis CD95 is differentially expres sed on distinct cell types and at different maturational stages with a n increase in receptor density from early CD34(+) stem cells to maturi ng progenitor cells. Incubation of bone marrow cells with anti-APO-1 ( anti-CD95) induces apoptosis in maturing erythroblasts and neutrophil progenitors (10-19%) and to a lesser extent in stem cells and myelobla st/proerythroblasts (4-9%). On in vitro culture, CD95 expression is pa rticularly upregulated on activated CD71(+) myeloid progenitors. Hemat opoietic cytokines (stem cell factor, interleukin-3, granulocyte macro phage colony-stimulating factor [GM-CSF], and granulocyte-colony stimu lating factor [G-CSF] contribute to upregulation of CD95 on bone marro w cells. CD95-induced apoptosis in activated progenitors was markedly enhanced by activating cytokines. Thus cytokines known to mediate prol iferation, survival, and maturation, in hematopoiesis do not prevent, but rather facilitate negative growth regulation via the CD95 pathway in activated cells. Deregulation of the CD95 system may provide a mole cular basis for the development of bone marrow failure or immune-media ted cytopenia. Defects in the CD95 pathway may contribute to the devel opment of hematopoietic malignancy by abrogating CD95-mediated growth control of activated cells.