Cutting edge: abortive proliferation of CD46-induced Tr1-like cells due to a defective Akt/Survivin signaling pathway.
T regulatory cell 1 (Tr1) are low proliferating peripherally induced suppressive T cells. Engaging CD3 and CD46 on human CD4+ T cells induces a Tr1-like phenotype. In this study, we report that human Tr1-like cells do not sustain proliferation over time. The weak proliferation of these cells results first from their inability to sustain expression of various cell cycle-associated proteins, to efficiently degrade the inhibitor of cell cycle progression p27/Kip1 and, as a consequence, in their accumulation in the G0-G1 phase. Also, the reduced proliferation of Tr1-like cells results from their increased sensitivity to death as they divide, through a mechanism that is neither Fas-mediated nor Bcl2/Bcl-xL related. Both properties, impaired cell cycle and death sensitivity, are explained by a specific defective activation of Akt that impairs the expression of Survivin. Thus, our results show that CD3/CD46-induced Tr1-like cells die through a process of abortive proliferation.
Meiffren
Grégory
G
Institut National de la Santé et de la Recherche Médicale Unité 503-IFR 128-BioSciences Lyon-Gerland-Université Claude-Bernard-Lyon 1, Lyon, France.
Flacher
Monique
M
Azocar
Olga
O
Rabourdin-Combe
Chantal
C
Faure
Mathias
M
D017252:CD3 Complex / Q000502:physiology; D002453:Cell Cycle; D016923:Cell Death; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051916:Membrane Cofactor Protein / Q000502:physiology*; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction; D000077022:Survivin; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*
C107489:BIRC5 protein, human; D017252:CD3 Complex; C436291:CDKN1B protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051916:Membrane Cofactor Protein; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051057:Proto-Oncogene Proteins c-akt