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Cyclin-dependent kinase 5 activity is required for allogeneic T cell responses after hematopoietic cell transplantation in mice

David Askew, Tej Pareek, Saada Eid, Sudipto Ganguly, Megan Tyler, Alex Y. Huang, John J. Letterio and Kenneth R. Cooke

Key points

  • Cdk5 function is required for optimal lymphocyte activation and migration following allogeneic HCT.

  • Targeting Cdk5 may be a particularly attractive strategy to reduce GVHD and maintain anti-tumor activity.

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 (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, pre-clinical, murine, GVHD model we reveal that Cdk5 activity is increased in key target organs early after allogeneic HCT. We then generated chimeric mice (Cdk5+/+C or Cdk5-/-C) using hematopoietic progenitors from either E16.5 Cdk5+/+ or Cdk5-/- embryos to enable analyses of the role of Cdk5 in GVHD, as germ line Cdk5 gene deletion is embryonically lethal. The immuno-phenotype of adult Cdk5-/-C mice is identical to control Cdk5+/+C mice. However, transplantation of donor Cdk5-/-C bone 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 (SLO), 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 SLO. Although Cdk5 activity in donor T cells contributed to GVT 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.

  • Submitted May 4, 2016.
  • Accepted October 16, 2016.