CDK4 Expression and Activity Are Required for Cytokine Responsiveness in T Cells

Abstract

Stimulation of lymphocytes through the Ag receptor can lead to cytokine responsiveness or unresponsiveness. We examined the importance of cyclin-dependent kinase (CDK)4 to establish and maintain IL-2 responsiveness in human T cells. Our results show that a herbimycin A- and staurosporine-sensitive phase of CDK4 expression and activity preceded the acquisition of IL-2-responsiveness in mitogen-stimulated peripheral blood T cells. Intriguingly, CDK4 expression and activity were demonstrable in purified unstimulated peripheral blood T cells from ∼30% (5/16) of healthy individuals examined for this study. These T cells proliferated in response to IL-2 without additional mitogens, and both the expression and activity of CDK4 and the ability to respond to cytokines were resistant to herbimycin A and staurosporine. The pattern of CDK4 expression and response to IL-2 in this subset of individuals resembled that seen in the human IL-2-dependent Kit-225 T cell line. However, in contrast to normal T cells, Kit-225 cells were rendered unresponsive to IL-2 by stimulation through the Ag receptor. In these cells, PHA, anti-CD3, or PMA induced marked reductions of CDK4 expression and activity that paralleled IL-2 unresponsiveness, and these effects were not reversible by IL-2. Furthermore, IL-2-dependent proliferation could be similarly inhibited in Kit-225 cells by overexpression of the CDK inhibitors p16/Ink4-a or p21/Waf-1a or by overexpression of a kinase-inactive CDK4 mutant. The data indicate that CDK4 expression and activity are necessary to induce and maintain cytokine responsiveness in T cells, suggesting that CDK4 is important to link T cell signaling pathways to the machinery that controls cell cycle progression.

Molecular Pathways: Targeting the Cyclin D–CDK4/6 Axis for Cancer Treatment

“…Preclinical studies showed that CDK4/6 inhibitor pretreatment protects both cancer cells and normal hematopoietic cells from death induced by ionizing radiation and other DNA-damaging agents (38). Similarly, antigen-stimulated T cells are dependent on CDK4/6 activity for proliferative expansion and differentiation (39), suggesting that combinations of CDK4/6 inhibitors with immune checkpoint inhibitors (e.g., anti-PD-1) will require careful evaluation for potential antagonism in preclinical models and human subjects.…”

Predictive value of p16 or Rb inactivation in a model of naturally occurring canine non-Hodgkin's lymphoma

“…It is known that these proteins contribute to the regulation of normal lymphocyte proliferation, possibly providing mechanisms that enforce quiescence, 15 but their precise role in the pathogenesis of NHL remains incompletely understood. In human NHL, alterations leading to p16 inactivation (deletion or promoter methylation) are commonly seen in blastoid mantle cell lymphoma; they occur less frequently in association with progression from mucosal associated lymphoid tissue lymphoma or follicular lymphoma to diffuse large B-cell lymphoma (DLBCL), and only sporadically in high-grade tumors.…”

Cyclin-Dependent Kinase 4 Hyperactivity Promotes Autoreactivity in the Immune System but Protects Pancreatic β Cell Mass from Autoimmune Destruction in the Nonobese Diabetic Mouse Model

“…Moreover, Cdk4 is clearly required for cytokine responsiveness in T cells (47). Surface markers on the lymphocyte and myeloid compartments in the prediabetic period reveal that both male and female NOD/Cdk4R24C cells present a more activated phenotype than WT gender-matched cells.…”