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p27kip1 functions as an anergy factor inhibiting interleukin 2 transcription and clonal expansion of alloreactive human and mouse helper T lymphocytes

Abstract

Although recent in vitro studies have begun to decipher the molecular events that characterize the anergic state, their in vivo biologic relevance and potential clinical importance remain unclear. Here, using anergic human T-cell clones and tolerant alloreactive mouse T cells that do not induce graft-versus-host disease, we show that p27kip1 cyclin-dependent kinase inhibitor is an essential regulator responsible for the blockade of clonal expansion of anergic T cells in vitro and in vivo. Moreover, in anergic cells, p27kip1 associates with the c-Jun co-activator JAB1, resulting in defective transactivation of AP-1 and interleukin 2 transcription. Therefore, pharmacological agents that upregulate the expression of or prevent the degradation of p27kip1 during antigen recognition should be part of new therapeutic strategies to induce antigen-specific T-cell unresponsiveness.

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Figure 1: Anergic T-cell clones are arrested at the early G1 phase of the cell cycle.
Figure 2: Increased intracellular cAMP results in inhibition of antigen-specific response and upregulation of p27kip1 in anergic T-cell clones.
Figure 3: p27kip1 inhibits T-cell clonal expansion and IL-2 secretion, and results in the induction of anergy.
Figure 4: IL-2 prevents the induction of anergy and rescues anergic T cells from unresponsiveness by downregulating p27kip1.
Figure 5: p27kip1 functions as a negative regulator of IL-2 transcription.
Figure 6: Upregulation of p27kip1 results in G1 arrest in tolerant mouse T cells.

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Acknowledgements

This study was supported by National Institutes of Health grants AI 43552, AI 41584, HL 54785, AI 34495 and HL 56067, and a research grant from the National Marrow Donor Program.

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Correspondence to Vassiliki A. Boussiotis.

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Boussiotis, V., Freeman, G., Taylor, P. et al. p27kip1 functions as an anergy factor inhibiting interleukin 2 transcription and clonal expansion of alloreactive human and mouse helper T lymphocytes. Nat Med 6, 290–297 (2000). https://doi.org/10.1038/73144

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