CD4-Lck through TCR and in the absence of Vav exchange factor induces Bax increase and mitochondrial damage.
In the present study, we aimed to demonstrate that CD4 may represent a critical turning point that governs the apoptotic and survival programs in T cells, without modifying the physical association with the TCR-CD3 complex. To address this issue, we have explored the possibility that the activation of CD4 may transduce apoptotic signals unless signaling effectors neutralize them. Our data show that in Jurkat T cells CD4 engagement by Leu3a mAb results in a rapid and strong increase of Lck kinase activity, subsequent alterations of mitochondrial membrane potential, and apoptosis. Critical parameters are coassociation of CD4/Lck with TCR/CD3 and up-regulation of the proapoptotic protein Bax. Indeed, Leu3a-mediated Lck activation failed to induce apoptotic features in Jurkat cells either defective for TCR/CD3 or overexpressing the antiapoptotic protein Bcl-2. Furthermore, we demonstrate that Leu3a treatment of Jurkat cells overexpressing Vav results in the inhibition of mitochondrial damage and apoptosis; this rescue effect is accompanied with a significant decrease of Bax expression observed in apoptotic cells. Our evidence that the activation of Lck activates in T cells apoptotic pathways which are counteracted by Vav, a signaling molecule that cooperates with CD28 to boost TCR signals, suggests a novel role for costimulation in protecting T cells from CD4-mediated cell death.
Tuosto
Loretta
L
Department of Cellular and Developmental Biology, La Sapienza University, Rome, Italy.
Marinari
Barbara
B
Piccolella
Enza
E
D000911:Antibodies, Monoclonal / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D018797:Cell Cycle Proteins; D015536:Down-Regulation / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007425:Intracellular Membranes / Q000276:immunology / Q000473:pathology; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism / Q000502:physiology*; D008564:Membrane Potentials / Q000276:immunology; D008928:Mitochondria / Q000276:immunology / Q000473:pathology*; D010539:Permeability; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology; D051567:Proto-Oncogene Proteins c-vav; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D014162:Transfection; D051028:bcl-2-Associated X Protein
D000911:Antibodies, Monoclonal; C494826:BAX protein, human; D015704:CD4 Antigens; D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051567:Proto-Oncogene Proteins c-vav; D017260:Receptor-CD3 Complex, Antigen, T-Cell; C496618:VAV1 protein, human; D051028:bcl-2-Associated X Protein; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)