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IL-7 promotes T cell proliferation through destabilization of p27Kip1

Wen, Qing Li ; Jiang, Qiong ; Aleem, Eiman ; Kaldis, Philipp LU orcid ; Khaled, Annette R. and Durum, Scott K. (2006) In Journal of Experimental Medicine 203(3). p.573-582
Abstract

Interleukin (IL)-7 is required for survival and homeostatic proliferation of T lymphocytes. The survival effect of IL-7 is primarily through regulation of Bcl-2 family members; however, the proliferative mechanism is unclear. It has not been determined whether the IL-7 receptor actually delivers a proliferative signal or whether, by promoting survival, proliferation results from signals other than the IL-7 receptor. We show that in an IL-7-dependent T cell line, cells protected from apoptosis nevertheless underwent cell cycle arrest after IL-7 withdrawal. This arrest was accompanied by up-regulation of the cyclin-dependent kinase inhibitor p27Kip1 through a posttranslational mechanism. Overexpression of p27Kip1... (More)

Interleukin (IL)-7 is required for survival and homeostatic proliferation of T lymphocytes. The survival effect of IL-7 is primarily through regulation of Bcl-2 family members; however, the proliferative mechanism is unclear. It has not been determined whether the IL-7 receptor actually delivers a proliferative signal or whether, by promoting survival, proliferation results from signals other than the IL-7 receptor. We show that in an IL-7-dependent T cell line, cells protected from apoptosis nevertheless underwent cell cycle arrest after IL-7 withdrawal. This arrest was accompanied by up-regulation of the cyclin-dependent kinase inhibitor p27Kip1 through a posttranslational mechanism. Overexpression of p27Kip1 induced G1 arrest in the presence of IL-7, whereas knockdown of p27Kip1 by small interfering RNA promoted S phase entry after IL-7 withdrawal. CD4 or CD8 T cells transferred into IL-7-deficient hosts underwent G1 arrest, whereas 27Kip1- deficient T cells underwent proliferation. We observed that IL-7 withdrawal activated protein kinase C (PKC)θ and that inhibition of PKCθ with a pharmacological inhibitor completely blocked the rise of p27Kip1 and rescued cells from G1 arrest. The conven tional pathway to breakdown of p27Kip1 is mediated by S phase kinase-associated protein 2; however, our evidence suggests that PKCθ acts via a distinct, unknown pathway inducing G1 arrest after IL-7 withdrawal from T cells. Hence, IL-7 maintains T cell proliferation through a novel pathway of p27Kip1 regulation.

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author
; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
in
Journal of Experimental Medicine
volume
203
issue
3
pages
573 - 582
publisher
Rockefeller University Press
external identifiers
  • pmid:16492801
  • scopus:33645064841
ISSN
0022-1007
DOI
10.1084/jem.20051520
language
English
LU publication?
no
id
b4024b6a-48ec-4204-9a92-7667017472ba
date added to LUP
2019-09-18 14:24:23
date last changed
2024-01-01 20:41:03
@article{b4024b6a-48ec-4204-9a92-7667017472ba,
  abstract     = {{<p>Interleukin (IL)-7 is required for survival and homeostatic proliferation of T lymphocytes. The survival effect of IL-7 is primarily through regulation of Bcl-2 family members; however, the proliferative mechanism is unclear. It has not been determined whether the IL-7 receptor actually delivers a proliferative signal or whether, by promoting survival, proliferation results from signals other than the IL-7 receptor. We show that in an IL-7-dependent T cell line, cells protected from apoptosis nevertheless underwent cell cycle arrest after IL-7 withdrawal. This arrest was accompanied by up-regulation of the cyclin-dependent kinase inhibitor p27<sup>Kip1</sup> through a posttranslational mechanism. Overexpression of p27<sup>Kip1</sup> induced G1 arrest in the presence of IL-7, whereas knockdown of p27<sup>Kip1</sup> by small interfering RNA promoted S phase entry after IL-7 withdrawal. CD4 or CD8 T cells transferred into IL-7-deficient hosts underwent G1 arrest, whereas 27<sup>Kip1</sup>- deficient T cells underwent proliferation. We observed that IL-7 withdrawal activated protein kinase C (PKC)θ and that inhibition of PKCθ with a pharmacological inhibitor completely blocked the rise of p27<sup>Kip1</sup> and rescued cells from G1 arrest. The conven tional pathway to breakdown of p27<sup>Kip1</sup> is mediated by S phase kinase-associated protein 2; however, our evidence suggests that PKCθ acts via a distinct, unknown pathway inducing G1 arrest after IL-7 withdrawal from T cells. Hence, IL-7 maintains T cell proliferation through a novel pathway of p27<sup>Kip1</sup> regulation.</p>}},
  author       = {{Wen, Qing Li and Jiang, Qiong and Aleem, Eiman and Kaldis, Philipp and Khaled, Annette R. and Durum, Scott K.}},
  issn         = {{0022-1007}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{3}},
  pages        = {{573--582}},
  publisher    = {{Rockefeller University Press}},
  series       = {{Journal of Experimental Medicine}},
  title        = {{IL-7 promotes T cell proliferation through destabilization of p27<sup>Kip1</sup>}},
  url          = {{http://dx.doi.org/10.1084/jem.20051520}},
  doi          = {{10.1084/jem.20051520}},
  volume       = {{203}},
  year         = {{2006}},
}