IL-7 promotes T cell proliferation through destabilization of p27Kip1
(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.
(Less)
- author
- Wen, Qing Li ; Jiang, Qiong ; Aleem, Eiman ; Kaldis, Philipp LU ; Khaled, Annette R. and Durum, Scott K.
- publishing date
- 2006-03-20
- 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}}, }