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

Tej K. Pareek, Eric Lam, Xiaojing Zheng, David Askew, Ashok B. Kulkarni, Mark R. Chance, Alex Y. Huang, Kenneth R. Cooke, John J. Letterio

Research output: Contribution to journalArticlepeer-review

Abstract

Cyclin-dependent kinase 5 (Cdk5) is a ubiquitously expressed serine/threonine kinase. However, a requirement for Cdk5 has been demonstrated only in postmitotic neurons where there is abundant expression of its activating partners p35 and/or p39. Although hyperactivation of the Cdk5-p35 complex has been found in a variety of inflammatory neurodegenerative disorders, the potential contribution of nonneuronal Cdk5-p35 activity has not been explored in this context. We describe a previously unknown function of the Cdk5-p35 complex in T cells that is required for induction of experimental autoimmune encephalomyelitis (EAE). T cell receptor (TCR) stimulation leads to a rapid induction of Cdk5-p35 expression that is required for T lymphocyte activation. Chimeric mice lacking Cdk5 gene expression in hematopoietic tissues (Cdk5 -/-C) are resistant to induction of EAE, and adoptive transfer of either Cdk5-/-C or p35-/- encephalitogenic lymphocytes fails to transfer disease. Moreover, our data reveal a novel mechanism involving Cdk5-mediated phosphorylation of the actin modulator coronin 1a on threonine 418. Cdk5-deficient lymphocytes lack this posttranslational modification of coronin 1a and exhibit defective TCR-induced actin polarization and reduced migration toward CCL-19. These data define a distinct role for Cdk5 in lymphocyte biology and suggest that inhibition of this kinase may be beneficial in the treatment of T cell-mediated inflammatory disorders.

Original languageEnglish (US)
Pages (from-to)2507-2519
Number of pages13
JournalJournal of Experimental Medicine
Volume207
Issue number11
DOIs
StatePublished - Oct 25 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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