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An Important Role of CDK Inhibitor p18^INK4c in Modulating Antigen Receptor-Mediated T Cell Proliferation¹

Grigoriy I. Kovalev^*,, David S. Franklin^2,*,, V. McNeil Coffield^*,, Yue Xiong^*, and Lishan Su^3,*,

^* Lineberger Comprehensive Cancer Center, Departments of Microbiology and Immunology, and Biochemistry and Biophysics, School of Medicine, University of North Carolina, Chapel Hill, NC 27599

The inhibitors of cyclin-dependent kinase (CDK) 4 (INK4) bind CDK4/6 to prevent their association with D-cyclins and G₁ cell cycle initiation and progression. We report here that among the seven CDK inhibitors, p18^INK4c played an important role in modulating TCR-mediated T cell proliferation. Loss of p18^INK4c in T cells led to hyperproliferation in response to CD3 stimulation. p18^INK4c-null mice developed lymphoproliferative disorder and T cell lymphomas. Expression of IL-2, IL-2R-, and the major G₁ cell cycle regulatory proteins was not altered in p18-null T cells. Both FK506 and rapamycin efficiently inhibited proliferation of p18-null T cells. In activated T cells, p18^INK4c remained constant, and preferentially associated with and inhibited CDK6 but not CDK4. We propose that p18^INK4c sets an inhibitory threshold in T cells and one function of CD28 costimulation is to counteract the p18^INK4c inhibitory activity on CDK6-cyclin D complexes. The p18^INK4c protein may provide a novel target to modulate T cell immunity.

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