Bcl-2 differentially regulates Ca2+ signals according to the strength of T cell receptor activation.
To investigate the effect of Bcl-2 on Ca2+ signaling in T cells, we continuously monitored Ca2+ concentration in Bcl-2-positive and -negative clones of the WEHI7.2 T cell line after T cell receptor (TCR) activation by anti-CD3 antibody. In Bcl-2-negative cells, high concentrations of anti-CD3 antibody induced a transient Ca2+ elevation, triggering apoptosis. In contrast, low concentrations of anti-CD3 antibody induced Ca2+ oscillations, activating the nuclear factor of activated T cells (NFAT), a prosurvival transcription factor. Bcl-2 blocked the transient Ca2+ elevation induced by high anti-CD3, thereby inhibiting apoptosis, but did not inhibit Ca2+ oscillations and NFAT activation induced by low anti-CD3. Reduction in the level of all three inositol 1,4,5-trisphosphate (InsP(3)) receptor subtypes by small interfering RNA inhibited the Ca2+ elevation induced by high but not low anti-CD3, suggesting that Ca2+ responses to high and low anti-CD3 may have different requirements for the InsP(3) receptor. Therefore, Bcl-2 selectively inhibits proapoptotic Ca2+ elevation induced by strong TCR activation without hindering prosurvival Ca2+ signals induced by weak TCR activation.
Zhong
Fei
F
Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Davis
Michael C
MC
McColl
Karen S
KS
Distelhorst
Clark W
CW
D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis; D017252:CD3 Complex / Q000276:immunology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000187:drug effects / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*
D000906:Antibodies; D017252:CD3 Complex; D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D018160:Receptors, Cytoplasmic and Nuclear; D002118:Calcium