HIV-1 trans-activator of transcription substitutes for oxidative signaling in activation-induced T cell death.
Termination of an immune response requires elimination of activated T lymphocytes by activation-induced cell death (AICD). In AICD, CD95 (Apo-1/Fas) ligand (L) triggers apoptosis of CD95-positive activated T lymphocytes. In AIDS patients, AICD is strongly enhanced and accelerated. We and others have previously shown that HIV-1 trans-activator of transcription (HIV-1 Tat) sensitizes T cells toward CD95-mediated apoptosis and up-regulates CD95L expression by affecting the cellular redox balance. In this study, we show that it is hydrogen peroxide (H(2)O(2)) that functions as an essential second messenger in TCR signaling. The H(2)O(2) signal combined with simultaneous calcium (Ca(2+)) influx into the cytosol constitutes the minimal requirement for induction of CD95L expression. Either signal alone is insufficient. We further show that HIV-1 Tat interferes with TCR signaling and induces a H(2)O(2) signal. H(2)O(2) generated by HIV-1 Tat combines with CD4-dependent calcium influx and causes massive T cell apoptosis. Thus, our data provide an explanation for CD4(+) T lymphocyte depletion during progression of AIDS.
Gülow
Karsten
K
Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.
Kaminski
Marcin
M
Darvas
Katalin
K
Süss
Dorothee
D
Li-Weber
Min
M
Krammer
Peter H
PH
D017209:Apoptosis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D020013:Calcium Signaling / Q000276:immunology*; D002614:Chelating Agents / Q000378:metabolism; D053222:Fas Ligand Protein; D005452:Fluoresceins / Q000378:metabolism; D015696:Gene Products, tat / Q000494:pharmacology / Q000502:physiology*; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018384:Oxidative Stress / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000494:pharmacology; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D054322:tat Gene Products, Human Immunodeficiency Virus
D002614:Chelating Agents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D005452:Fluoresceins; D015696:Gene Products, tat; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011994:Recombinant Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; C085925:calcein AM; D006861:Hydrogen Peroxide; D002118:Calcium