CD28 costimulation mediates T cell expansion via IL-2-independent and IL-2-dependent regulation of cell cycle progression.
In the presence of TCR ligation by Ag, CD28 pathway mediates the most potent costimulatory signal for T cell activation, cytokine secretion, and T cell expansion. Although CD28 costimulation promotes T cell expansion due to IL-2 secretion and subsequent signaling via the IL-2 receptor, recent studies indicate that the dramatic T cell expansion mediated through the unopposed CD28 stimulation in CTLA4-deficient mice is IL-2 independent. Therefore, we sought to dissect the effects of CD28 and IL-2 receptor pathways on cell cycle progression and determine the molecular mechanisms by which the CD28 pathway regulates T cell expansion. Here we show that CD28 costimulation directly regulates T cell cycle entry and progression through the G1 phase in an IL-2-independent manner resulting in activation of cyclin D2-associated cdk4/cdk6 and cyclin E-associated cdk2. Subsequent progression into the S phase is mediated via both IL-2-dependent and IL-2-independent mechanisms and, although in the absence of IL-2 the majority of T cells are arrested at the G1/S transition, a significant fraction of them progresses into the S phase. The key regulatory mechanism for the activation of cyclin-cdk complexes and cell cycle progression is the down-regulation of p27kip1 cdk inhibitor, which is mediated at the posttranscriptional level by its ubiquitin-dependent degradation in the proteasome pathway. Therefore, CD28 costimulation mediates T cell expansion in an IL-2-independent and IL-2 dependent manner and regulates cell cycle progression at two distinct points: at the early G1 phase and at the G1/S transition.
Appleman
L J
LJ
Department of Adult Oncology, Dana-Farber Cancer Institute, Division of Medical Oncology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Berezovskaya
A
A
Grass
I
I
Boussiotis
V A
VA
D018106:CD28 Antigens / Q000502:physiology*; D002453:Cell Cycle / Q000276:immunology*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D016193:G1 Phase / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000502:physiology*; D008213:Lymphocyte Activation; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D009097:Multienzyme Complexes / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011499:Protein Processing, Post-Translational / Q000235:genetics / Q000276:immunology; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins / Q000378:metabolism
D018106:CD28 Antigens; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D008869:Microtubule-Associated Proteins; D009097:Multienzyme Complexes; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex