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 poten t costimulatory signal for T cell activation, cytokine secretion, and T cel l expansion, Although CD28 costimulation promotes T cell expansion due to I L-2 secretion and subsequent signaling via the IL-2 receptor, recent studie s indicate that the dramatic T cell expansion mediated through the unoppose d 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 d irectly regulates T cell cycle entry and progression through the G(1) phase in an IL-2-independent manner resulting in activation of cyclin D2-associa ted cdk4/cdk6 and cyclin E-associated cdk2. Subsequent progression into the S phase is mediated via both IL-2-dependent and IL-2-independent mechanism s 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 t he S phase. The key regulatory mechanism for the activation of cyclin-cdk c omplexes and cell cycle progression is the down-regulation of p27(kip1) cdk inhibitor, which is mediated at the posttranscriptional level by its ubiqu itin-dependent degradation in the proteasome pathway Therefore, CD28 costim ulation 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.