CD28 induces cell cycle progression by IL-2-independent down-regulation of p27kip1 expression in human peripheral T lymphocytes

Boonen, G. J. J. C.; Dijk, Astrid M. C. van; Verdonck, Leo F.; Lier, René A. W. van; Rijksen, Gert; Medema, René H.

doi:10.1002/(sici)1521-4141(199903)29:03<789::aid-immu789>3.3.co;2-x

Cited by 9 publications

(14 citation statements)

References 9 publications

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“…These holoenzymes are inhibited by CDKIs; specifically, p27kip1, which is constitutively expressed in resting naïve T cells, inhibits the activities of cyclinD2/cdk4/6 and cyclinE/cdk2 (27). Therefore, cell cycle progression depends on the down-regulation of p27kip1, in addition to the up-regulation of cyclins.…”

Section: Resultsmentioning

confidence: 99%

Cell Cycle Progression following Naive T Cell Activation Is Independent of Jak3/Common γ-Chain Cytokine Signals

Shi

Lin²,

Appell³

et al. 2009

The Journal of Immunology

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T cell proliferation following activation is an essential aspect of the adaptive immune response. Multiple factors, such as TCR signaling, costimulation, and signals from cytokines, each contribute to determine the magnitude of T cell expansion. In this report, we examine in detail the role of Jak3/common γ-chain-dependent cytokines in promoting cell cycle progression and proliferation of naive T cells. Using naive CD4+ T cells from Jak3-deficient mice and wild-type CD4+ T cells treated with a small molecule inhibitor of Jak3, we find that these cytokine signals are not required for proliferation; instead, they are important for the survival of activated T cells. In addition, we show that the percentage of cells entering the cell cycle and the percentage of cells in each round of cell division are comparable between Jak3-deficent and wild-type T cells. Furthermore, cell cycle progression and the regulated expression of key cell cycle proteins are independent of Jak3/common γ-chain cytokine signals. These findings hold true over a wide range of TCR signal strengths. However, when CD28 costimulatory signals, but not TCR signals, are limiting, Jak3-dependent cytokine signals become necessary for the proliferation of naive T cells. Because CD28 signaling has been found to be dispensable for autoreactive T cell responses, these data suggest the potential for interfering with autoimmune T cell responses by inhibition of Jak3 signaling.

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Section: Resultsmentioning

confidence: 99%

Cell Cycle Progression following Naive T Cell Activation Is Independent of Jak3/Common γ-Chain Cytokine Signals

Shi

Lin²,

Appell³

et al. 2009

The Journal of Immunology

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“…In addition, PKA I inhibits cyclin D3 expression and induces the cyclin‐dependent kinase inhibitor p27 kip1 . 22 Synthesis of D‐type cyclins, including cyclin D3, during the G 1 phase of the cell cycle is required for progression of T cells from G 1 into S phase 23,24 . The D‐type cyclins bind cyclin‐dependent kinase (Cdk), forming an active kinase complex that phosphorylates and inactivates retinoblastoma protein (pRb) 25,26 .…”

Section: Introductionmentioning

confidence: 99%

“…However, cyclin D/Cdk complexes can associate with the Cdk inhibitor, p27 kip1 , leading to their inactivation 27,28 . In addition to cyclin D induction, T‐cell proliferation requires p27 kip1 down‐regulation 24,27 , 28 . Thus, PKA I‐mediated inhibition of cyclin D3 expression and induction of p27 kip1 block T‐cell cycle progression.…”

Section: Introductionmentioning

confidence: 99%

T cell receptor induced intracellular redistribution of type I protein kinase A

Zhou¹,

Vergara²,

König

2004

Immunology

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SUMMARYThe productive activation of CD4 + T lymphocytes, leading to proliferation and cytokine secretion, requires precise temporal regulation of intracellular cyclic AMP concentrations. The major effector molecule activated by cyclic AMP in mammalian cells is the cyclic AMPdependent protein kinase A (PKA). The type I PKA isozyme mediates the inhibitory effects of cyclic AMP on T-cell activation. Using laser scanning confocal microscopy, we demonstrated that the regulation of PKA type I activity involves spatial redistribution of PKA type I molecules following T-cell receptor (TCR) stimulation. In resting T cells, PKA type I was located in membrane proximal regions and distributed equally across the cell. Shortly after antigen engagement, T cells and antigen-presenting cells formed an area of intense contact, known as the immunological synapse. TCR concentrated at the synapse, whereas PKA type I molecules redistributed to the opposite cell pole within 10 min after T-cell stimulation. Type I PKA redistribution was solely dependent on TCR signalling, because we observed the same temporal and spatial distribution after antibody-mediated cross-linking of the TCR-associated CD3 complex. Segregation of TCR and PKA type I molecules was maintained for at least 20 min. Thirty minutes after stimulation, PKA type I partially colocalized with the TCR. After 60 min, PKA type I distribution again approached the resting state. Considering that initial TCR signals lead to increases in intracellular cyclic AMP, PKA type I molecules may be targeted towards localized cyclic AMP accumulations or transported away from these areas, depending on the requirements of the cellular response.

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“…CTLA-4 engagement prevents p27 Kip1 degradation [68,343] while rapamycin exposure inhibits p27 Kip1 downregulation following IL-2R engagement [344,345] and n-butyrate treatment causes the accumulation of both p21 Cip1 and p27 Kip1 [346]. Conversely, IL-2 stimulates p27 Kip1 degradation [347] as does the engagement of the costimulatory molecules CD28 [348][349][350] and 4-1BB [351,352]. Primed p27 Kip1-/-T-cells are more responsive to IL-2 exposure and both produce more IL-2 and proliferate more strongly in response to secondary stimulation in vitro [353].…”

Section: Cell Cycle Blockadementioning

confidence: 99%

The Biochemical Mechanisms of T-Cell Anergy

Atfield¹,

Liu²,

Penninger

2006

CIR

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T-cells are thought to play important roles in the coordination and development of immune responses in both health and disease. A key checkpoint in the prevention of inappropriate activation of T-cells is the requirement for costimulation by professional APCs via receptors such as CD28. Several in vivo and in vitro methods of experimental anergy induction have been developed and are in popular use today. However, the biochemical events that determine Tcell fate following the application of activating vs. anergizing stimuli remain poorly understood. We present a survey of T-cell signal transduction in productive encounters with antigen-presenting cells, as well as the molecular mechanisms that are thought to alter these signaling pathways in T-cell anergy and the conceptual and experimental context in which this understanding has been developed. A strong possibility is that the program of anergy induction involves the upregulation of one or more 'anergy factors' and over the years, several possible mechanisms of T-cell anergy have been proposed. Amongst these, E3 ubiquitin ligases such as Cbl-b, Itch and GRAIL have recently emerged as being essential players in T-cell tolerance, as well as host survival.

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CD28 induces cell cycle progression by IL-2-independent down-regulation of p27kip1 expression in human peripheral T lymphocytes

Cited by 9 publications

References 9 publications

Cell Cycle Progression following Naive T Cell Activation Is Independent of Jak3/Common γ-Chain Cytokine Signals

Cell Cycle Progression following Naive T Cell Activation Is Independent of Jak3/Common γ-Chain Cytokine Signals

T cell receptor induced intracellular redistribution of type I protein kinase A

The Biochemical Mechanisms of T-Cell Anergy

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