p21Cip1 and p27Kip1 act in synergy to alter the sensitivity of naive T cells to TGF-beta-mediated G1 arrest through modulation of IL-2 responsiveness.
Induction of G(1) arrest by TGF-beta correlates with the regulation of p21(Cip1) and p27(Kip1), members of the Cip/Kip family of cyclin-dependent kinase inhibitors (cki). However, no definitive evidence exists that these proteins play a causal role in TGF-beta(1)-induced growth arrest in lymphocytes. In this report we show the suppression of cell cycle progression by TGF-beta is diminished in T cells from mice deficient for both p21(Cip1) and p27(Kip1) (double-knockout (DKO)) only when activated under conditions of optimal costimulation. Although there is an IL-2-dependent enhanced proliferation of CD8(+) T cells from DKO mice, TGF-beta is able to maximally suppress the proliferation of DKO T cells when activated under conditions of low costimulatory strength. We also show that the induction of p15(Ink4b) in T cells stimulated in the presence of TGF-beta is not essential, as TGF-beta also efficiently suppressed proliferation of T cells from p15(Ink4b-/-) mice. Finally, although these cki are dispensable for the suppression of T cell proliferation by TGF-beta, we now describe a Smad3-dependent down-regulation of cdk4, suggesting a potential mechanism underlying to resistance of Smad3(-/-) T cells to the induction of growth arrest by TGF-beta. In summary, the growth suppressive effects of TGF-beta in naive T cells are a function of the strength of costimulation, and alterations in the expression of cki modify the sensitivity to TGF-beta by lowering thresholds for a maximal mitogenic response.
Wolfraim
Lawrence A
LA
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. wolfraim@tolergenics.com
Walz
Thomas M
TM
James
Zakiya
Z
Fernandez
Tania
T
Letterio
John J
JJ
D000818:Animals; D018797:Cell Cycle Proteins / Q000276:immunology / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4; D050762:Cyclin-Dependent Kinase Inhibitor p15; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000276:immunology / Q000378:metabolism; D016213:Cyclins / Q000276:immunology / Q000378:metabolism*; D015536:Down-Regulation; D016193:G1 Phase / Q000276:immunology / Q000502:physiology*; D007156:Immunologic Memory / Q000276:immunology / Q000502:physiology; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism*; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation
C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; C493968:Cdkn2b protein, mouse; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D007376:Interleukin-2; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases