Induction of Anergy in Th1 Cells Associated with Increased Levels of Cyclin-Dependent Kinase Inhibitors p21Cip1 and p27Kip1 1

Jackson, Stephanie K.; DeLoose, Annick; Gilbert, Kathleen M.

doi:10.4049/jimmunol.166.2.952

Cited by 48 publications

(66 citation statements)

References 27 publications

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“…Anergy can also be induced by pharmacological inhibitors that do not block costimulatory signals, but rather interfere with cell cycle progression in G 1 phase or interfere with growth-factor receptor signal transduction. Such pharmacologically induced anergy is also associated with elevation of p27 kip1 , suggesting a critical link between p27 kip1 down-regulation and avoidance of anergy induction (4,10,13).…”

mentioning

confidence: 99%

The Cyclin-Dependent Kinase Inhibitor p27kip1 Is Required for Transplantation Tolerance Induced by Costimulatory Blockade

Rowell

Wang

Hancock

et al. 2006

The Journal of Immunology

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The cyclin-dependent kinase (CDK) inhibitor p27kip1 is an important negative regulator of the cell cycle that sets a threshold for mitogenic signals in T lymphocytes, and is required for T cell anergy in vitro. To determine whether p27kip1 is required for tolerance in vivo, we performed cardiac allograft transplantation under conditions of combined CD28/CD40L costimulatory blockade. Although this treatment induced long-term allograft survival in wild-type recipients, costimulatory blockade was no longer sufficient to induce tolerance in mice lacking p27kip1. Rejected allografts from p27kip1−/− mice contained more CD4+ T lymphocytes and exhibited more tissue damage than allografts from tolerant, wild-type mice. Infiltrating p27kip1-deficient T cells, but not wild-type T cells, exhibited nuclear expression of cyclins E and A, indicating uncontrolled T cell cycle progression in the graft. The failure of tolerance in p27kip1−/− mice was also accompanied by markedly increased numbers of allospecific, IFN-γ-producing cells in the periphery, and occurred despite apparently normal regulatory T cell activity. These data demonstrate that the CDK inhibitor p27kip1 enforces the costimulatory requirement for the expansion and differentiation of alloimmune effector T lymphocytes in vivo, and point to CDKs as novel targets for immunosuppressive or tolerance-inducing therapies.

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mentioning

confidence: 99%

The Cyclin-Dependent Kinase Inhibitor p27kip1 Is Required for Transplantation Tolerance Induced by Costimulatory Blockade

Rowell

Wang

Hancock

et al. 2006

The Journal of Immunology

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“…For instance, a number of reports have indicated the G 1 cyclin-dependent kinase inhibitor p27 Kip as a putative anergic factor, because its deregulated expression directly correlates with T cell responsiveness (15,16). Indeed, suboptimal stimulation with costimulatory deficient APC, which results in T cell anergy, fails to downregulate p27 Kip and elicits cell cycle arrest in early G 1 (15).…”

mentioning

confidence: 99%

Clonal Anergy Is Maintained Independently of T Cell Proliferation

Colombetti

Benigni

Basso

et al. 2002

The Journal of Immunology

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Ag encounter in the absence of proliferation results in the establishment of T cell unresponsiveness, also known as T cell clonal anergy. Anergic T cells fail to proliferate upon restimulation because of the inability to produce IL-2 and to properly regulate the G1 cell cycle checkpoint. Because optimal TCR and CD28 engagement can elicit IL-2-independent cell cycle progression, we investigated whether CD3/CD28-mediated activation of anergic T cells could overcome G1 cell cycle block, drive T cell proliferation, and thus reverse clonal anergy. We show here that although antigenic stimulation fails to elicit G1-to-S transition, anti-CD3/CD28 mAbs allow proper cell cycle progression and proliferation of anergic T cells. However, CD3/CD28-mediated cell division does not restore Ag responsiveness. Our data instead indicate that reversal of clonal anergy specifically requires an IL-2-dependent, rapamycin-sensitive signal, which is delivered independently of cell proliferation. Thus, by tracing proliferation and Ag responsiveness of individual cells, we show that whereas both TCR/CD28 and IL-2-generated signals can drive T cell proliferation, only IL-2/IL-2R interaction regulates Ag responsiveness, indicating that proliferation and clonal anergy can be independently regulated.

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“…CD4+, rather than CD8+ T cells appear to be more inhibited by p21 (1,2). Finally, high levels of both p27 and p21 are present in anergic T cells (10,36), reflecting induction of p21 as well as a failure to down-regulate p27.…”

Section: Discussionmentioning

confidence: 99%

“…Upregulation of p21 has been observed in memory CD4+ T cells and in T cells after several rounds of proliferation and chronic activation (1). Further, p21, along with p27, is upregulated in anergic T cells (10). Thus, cdk inhibitors are considered potent suppressors of immune responses and may therefore be therapeutically important in transplantation and autoimmunity.…”

Section: Introductionmentioning

confidence: 99%

“…Hence, the Cip/Kip family of cdk inhibitors is believed to regulate G 1 and S phase cdks in vivo. Indeed, p21 and p27 have been shown to be important for cell cycle control of a variety of cell types, including T cells (7)(8)(9)(10). Zhang et al (9) reported that p27 controlled cytokine-induced T cell proliferation, while p21 played a lesser role in this process.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of alloimmune Th1 responses by the cyclin-dependent kinase inhibitor p21 following transplantation

Welling

Csencsits

et al. 2008

Surgery

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Background-The cyclin-dependent kinase (cdk) inhibitor p21 inhibits cellular proliferation of many cell types, including T cells. However, autoimmune models have yielded conflicting results regarding the role of cdk inhibitors and T cell function. The role of p21 in T cell function following transplantation has not been directly investigated. We hypothesized that p21 plays an important role in alloantigen-driven responses in vitro in mixed lymphocyte cultures (MLC) and in vivo using the heterotopic murine cardiac allograft model.

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Induction of Anergy in Th1 Cells Associated with Increased Levels of Cyclin-Dependent Kinase Inhibitors p21Cip1 and p27Kip1 1

Cited by 48 publications

References 27 publications

The Cyclin-Dependent Kinase Inhibitor p27kip1 Is Required for Transplantation Tolerance Induced by Costimulatory Blockade

The Cyclin-Dependent Kinase Inhibitor p27kip1 Is Required for Transplantation Tolerance Induced by Costimulatory Blockade

Clonal Anergy Is Maintained Independently of T Cell Proliferation

Regulation of alloimmune Th1 responses by the cyclin-dependent kinase inhibitor p21 following transplantation

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