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p21^Cip1 and p27^Kip1 Act in Synergy to Alter the Sensitivity of Naive T Cells to TGF--Mediated G₁ Arrest through Modulation of IL-2 Responsiveness

Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

Induction of G₁ arrest by TGF- 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-₁-induced growth arrest in lymphocytes. In this report we show the suppression of cell cycle progression by TGF- 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- 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- is not essential, as TGF- 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-, 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-. In summary, the growth suppressive effects of TGF- in naive T cells are a function of the strength of costimulation, and alterations in the expression of cki modify the sensitivity to TGF- by lowering thresholds for a maximal mitogenic response.

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