RT Journal Article SR Electronic T1 An Important Role of CDK Inhibitor p18INK4c in Modulating Antigen Receptor-Mediated T Cell Proliferation JF The Journal of Immunology JO J. Immunol. FD American Association of Immunologists SP 3285 OP 3292 DO 10.4049/jimmunol.167.6.3285 VO 167 IS 6 A1 Kovalev, Grigoriy I. A1 Franklin, David S. A1 Coffield, V. McNeil A1 Xiong, Yue A1 Su, Lishan YR 2001 UL http://www.jimmunol.org/content/167/6/3285.abstract AB 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, p18INK4c played an important role in modulating TCR-mediated T cell proliferation. Loss of p18INK4c in T cells led to hyperproliferation in response to CD3 stimulation. p18INK4c-null mice developed lymphoproliferative disorder and T cell lymphomas. Expression of IL-2, IL-2R-α, 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, p18INK4c remained constant, and preferentially associated with and inhibited CDK6 but not CDK4. We propose that p18INK4c sets an inhibitory threshold in T cells and one function of CD28 costimulation is to counteract the p18INK4c inhibitory activity on CDK6-cyclin D complexes. The p18INK4c protein may provide a novel target to modulate T cell immunity.