CXCR4 and CD4 mediate a rapid CD95-independent cell death in CD4(+) T cells.
AIDS is characterized by a progressive decrease of CD4(+) helper T lymphocytes. Destruction of these cells may involve programmed cell death, apoptosis. It has previously been reported that apoptosis can be induced even in noninfected cells by HIV-1 gp120 and anti-gp120 antibodies. HIV-1 gp120 binds to T cells via CD4 and the chemokine coreceptor CXCR4 (fusin/LESTR). Therefore, we investigated whether CD4 and CXCR4 mediate gp120-induced apoptosis. We used human peripheral blood lymphocytes, malignant T cells, and CD4/CXCR4 transfectants, and found cell death induced by both cell surface receptors, CD4 and CXCR4. The induced cell death was rapid, independent of known caspases, and lacking oligonucleosomal DNA fragmentation. In addition, the death signals were not propagated via p56(lck) and Gialpha. However, the cells showed chromatin condensation, morphological shrinkage, membrane inversion, and reduced mitochondrial transmembrane potential indicative of apoptosis. Significantly, apoptosis was exclusively observed in CD4(+) but not in CD8(+) T cells, and apoptosis triggered via CXCR4 was inhibited by stromal cell-derived factor-1, the natural CXCR4 ligand. Thus, this mechanism of apoptosis might contribute to T cell depletion in AIDS and might have major implications for therapeutic intervention.
Tumor Immunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
C
C
Berndt
B
B
Möpps
S
S
Angermüller
P
P
Gierschik
P H
PH
Krammer
D017209:Apoptosis / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D006801:Humans; D019169:Jurkat Cells; D019718:Receptors, CXCR4 / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000276:immunology*
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D019718:Receptors, CXCR4; D019014:fas Receptor; D019206:GTP-Binding Protein alpha Subunits, Gi-Go