title: Regulation of T cell differentiation and alloimmunity by the cyclin-dependent kinase inhibitor p18ink4c.
abstract: Cellular proliferation in response to mitogenic stimuli is negatively regulated by the Cip/Kip and the Ink4 families of cyclin-dependent kinase (CDK) inhibitors. Several of these proteins are elevated in anergic T cells, suggesting a potential role in the induction or maintenance of tolerance. Our previous studies showed that p27kip1 is required for the induction of T cell anergy and transplantation tolerance by costimulatory blockade, but a role for Ink4 proteins in these processes has not been established. Here we show that CD4+ T cells from mice genetically deficient for p18ink4c divide more rapidly than wild-type cells in response to antigenic, costimulatory and growth factor signals. However, this gain of proliferative function was accompanied by a moderate increase in the rate of cell death, and was accompanied by an overall defect in the generation of alloreactive IFNγ-producing effector cells. Consistent with this, p18ink4c-deficient T cells were unable to induce graft-vs-host disease in vivo, and p18ink4c deficiency cooperated with costimulatory blockade to significantly increase the survival of fully mismatched allografts in a cardiac transplantation model. While both p18ink4c and p27kip1 act to restrict T cell proliferation, p18ink4c exerts an opposite effect from p27kip1 on alloimmunity and organ transplant rejection, most likely by sustaining T cell survival and the development of effector function. Our studies point to additional important links between the cell cycle machinery and the processes of T cell differentiation, survival and tolerance.
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Rowell
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: Liqing
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: Neelanjana
authors.initials: N
authors.lastname: Chunder
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Wells
mesh_terms: D064591:Allografts / Q000276:immunology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002453:Cell Cycle; D002454:Cell Differentiation / Q000276:immunology*; D017635:Clonal Anergy / Q000276:immunology; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D007109:Immunity; D007700:Kinetics; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015398:Signal Transduction
chemical_list: D050763:Cyclin-Dependent Kinase Inhibitor p18; D016207:Cytokines; D004247:DNA