An important role of CDK inhibitor p18INK4c in modulating antigen receptor-mediated T cell proliferation

G. I. Kovalev, D. S. Franklin, V. M. Coffield, Y. Xiong, L. Su

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3285-3292
Number of pages8
JournalJournal of Immunology
Volume167
Issue number6
DOIs
Publication statusPublished - 15 Sep 2001
Externally publishedYes

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