Journal
JOURNAL OF IMMUNOLOGY
Volume 164, Issue 1, Pages 144-151Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.164.1.144
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Funding
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P50HL054785] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [P01AI041584, R56AI043552, R21AI043552, R01AI043552] Funding Source: NIH RePORTER
- NHLBI NIH HHS [HL 54785] Funding Source: Medline
- NIAID NIH HHS [AI 43552, AI 41584] Funding Source: Medline
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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 G(1) 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 G(1)/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 p27(kip1) 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 G(1) phase and at the G(1)/S transition.
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