title: An important role of CDK inhibitor p18(INK4c) in modulating antigen receptor-mediated T cell proliferation.
abstract: The inhibitors of cyclin-dependent kinase (CDK) 4 (INK4) bind CDK4/6 to prevent their association with D-cyclins and G(1) 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-alpha, and the major G(1) 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.
authors.affiliation: Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: G I
authors.initials: GI
authors.lastname: Kovalev
authors.forename: D S
authors.initials: DS
authors.lastname: Franklin
authors.forename: V M
authors.initials: VM
authors.lastname: Coffield
authors.forename: Y
authors.initials: Y
authors.lastname: Xiong
authors.forename: L
authors.initials: L
authors.lastname: Su
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002455:Cell Division; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D050763:Cyclin-Dependent Kinase Inhibitor p18; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology*; D016399:Lymphoma, T-Cell / Q000235:genetics; D008232:Lymphoproliferative Disorders / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D020123:Sirolimus / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; C493972:Cdkn2c protein, mouse; D018797:Cell Cycle Proteins; D050763:Cyclin-Dependent Kinase Inhibitor p18; D016207:Cytokines; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases; D020123:Sirolimus; D016559:Tacrolimus