title: Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice.
abstract: Molecular intermediates in T-cell activation pathways are crucial targets for the therapy and prevention of graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (allo-HCT). We recently identified an essential role for cyclin-dependent kinase 5 (Cdk5) in T-cell activation and effector function, but the contribution of Cdk5 activity to the development of GVHD has not been explored. Using an established, preclinical, murine, GVHD model, we reveal that Cdk5 activity is increased in key target organs early after allo-HCT. We then generated chimeric mice (Cdk5+/+Cor Cdk5-/-C) using hematopoietic progenitors from either embryonic day 16.5 Cdk5+/+or Cdk5-/-embryos to enable analyses of the role of Cdk5 in GVHD, as germ line Cdk5 gene deletion is embryonically lethal. The immunophenotype of adult Cdk5-/-Cmice is identical to control Cdk5+/+Cmice. However, transplantation of donor Cdk5-/-Cbone marrow and T cells dramatically reduced the severity of systemic and target organ GVHD. This phenotype is attributed to decreased T-cell migration to secondary lymphoid organs (SLOs), reduced in vivo proliferation within these organs, and fewer cytokine-producing donor T cells during GVHD development. Moreover, these defects in Cdk5-/-T-cell function are associated with altered CCR7 signaling following ligation by CCL19, a receptor:ligand interaction critical for T-cell migration into SLOs. Although Cdk5 activity in donor T cells contributed to graft-versus-tumor effects, pharmacologic inhibition of Cdk5 preserved leukemia-free survival. Collectively, our data implicate Cdk5 in allogeneic T-cell responses after HCT and as an important new target for therapeutic intervention.
authors.affiliation: Division of Hematology/Oncology, Department of Pediatrics, Case Western Reserve University, Cleveland, OH.|The Angie Fowler Adolescent & Young Adult Cancer Institute, Cleveland, OH.
authors.forename: David
authors.identifier: 0000-0001-7272-2019
authors.initials: D
authors.lastname: Askew
authors.affiliation: Division of Hematology/Oncology, Department of Pediatrics, Case Western Reserve University, Cleveland, OH.|The Angie Fowler Adolescent & Young Adult Cancer Institute, Cleveland, OH.
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pareek
authors.affiliation: Division of Hematology/Oncology, Department of Pediatrics, Case Western Reserve University, Cleveland, OH.|The Angie Fowler Adolescent & Young Adult Cancer Institute, Cleveland, OH.
authors.forename: Saada
authors.initials: S
authors.lastname: Eid
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD.
authors.forename: Sudipto
authors.initials: S
authors.lastname: Ganguly
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD.
authors.forename: Megan
authors.initials: M
authors.lastname: Tyler
authors.affiliation: Division of Hematology/Oncology, Department of Pediatrics, Case Western Reserve University, Cleveland, OH.|The Angie Fowler Adolescent & Young Adult Cancer Institute, Cleveland, OH.|Department of Pathology, Case Western Reserve University, Cleveland, OH; and.|Case Comprehensive Cancer Center, School of Medicine and.
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Huang
authors.affiliation: Division of Hematology/Oncology, Department of Pediatrics, Case Western Reserve University, Cleveland, OH.|Case Comprehensive Cancer Center, School of Medicine and.|Department of Pharmacology, Case Western Reserve University, Cleveland, OH.
authors.forename: John J
authors.initials: JJ
authors.lastname: Letterio
authors.affiliation: Division of Hematology/Oncology, Department of Pediatrics, Case Western Reserve University, Cleveland, OH.|The Angie Fowler Adolescent & Young Adult Cancer Institute, Cleveland, OH.|Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Cooke
mesh_terms: D064591:Allografts; D000818:Animals; D015153:Blotting, Western; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D051360:Cyclin-Dependent Kinase 5 / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D007938:Leukemia / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse