Cyclin-dependent kinase 5 activity is required for T cell activation and induction of experimental autoimmune encephalomyelitis

Abstract

Cyclin-dependent kinase 5 drives T cell activation and disease in EAE in part by regulating the actin binding protein coronin 1a.

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

“…Female C57BL/6J (B6; H-2 b ) and B6D2F1 (F1; H-2 bxd ) mice aged 8 to 12 weeks were purchased from The Jackson Laboratory (Bar Harbor, ME). Detailed methods for the generation of Cdk5-null hematopoietic chimeras, 13 immunoprecipitation and Cdk5 kinase activity assay, 25 T-cell isolation and BM transplant (BMT) procedures, 33 mixed lymphocyte reactions, T-cell proliferation and cytolytic activity, 33,34 assessment of clinical 35 and target organ GVHD, 33 in vivo graft-versus-leukemia (GVL) models, 33,34 bioluminescent imaging techniques, 34,36 and statistical analysis have been previously described and are outlined in supplemental Methods (available on the Blood Web site).…”

“…33,34,37,38 We first assessed whether enhanced Cdk5 activity could be detected during early stages of GVHD as described in supplemental Methods. 13 Cdk5 activity was notably increased by day 10 after allo-HCT in the spleen and small intestine, established sites of activation, and initial recruitment of donor T cells (Figure 2A HCT (Figure 2B-C; P , .01). These findings were accompanied by a reduction in donor T-cell expansion on days 3, 7, and 14 in alloCdk5 2/2C recipients ( Figure 2D) correlating with decreases in day 7 serum interferon g (IFNg) levels ( Figure 2E) and significant reductions in inflammation in key GVHD target organs ( Figure 2F).…”

“…13 Three months after embryo transfer, spleen, lymph nodes (LNs), and thymus were harvested from fully engrafted, Cdk5 1/1C and Cdk5…”

“…We have previously shown that Cdk5 gene deletion impairs T-cell migration to CCL19 in vitro. 13 CCL19 specifically binds to CCR7 and is important in directing the migration of naive T cells to SLOs. 39 Intracellularly, the ERK pathway contributes to CCL19-and CCL21-generated signals governing cell survival and migration, [40][41][42] and it is known that Cdk5 can suppress ERKs through direct action on a novel site in the MAPK/ ERK kinase (MEK).…”

“…Rather, Cdk5 interacts with its obligate partner proteins, p35 and p39, [10][11][12][13] whose constitutive expression in postmitotic neurons is essential for the many known functions of Cdk5 in the regulation of cytoarchitecture, synaptic function, and dopamine signaling in the central nervous system. Physiologic Cdk5 activity is essential in neuronal development, [14][15][16][17] memory, and neurogenesis, 16 whereas aberrant hyperactivity of Cdk5 has been linked with neurodegenerative disorders 11,[18][19][20][21] Data from our laboratory and others have implicated Cdk5 in immune dysregulation 13,22,23 and inflammatory pain signaling activated by tumor necrosis factor a (TNFa) through mechanisms that include transcriptional upregulation of p35. 24,25 We recently demonstrated a role for Cdk5 in posttranslational modification of proteins triggered by T-cell receptor (TCR) and chemokine receptor signaling and required for optimal immune synapse formation, cellular activation, and migratory capacity.…”