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Volume 272, Number 50, Issue of December 12, 1997 pp. 31809-31820

The Ca²⁺/Calmodulin-dependent Kinase Type IV Is Involved in the CD5-mediated Signaling Pathway in Human T Lymphocytes

(Received for publication, April 23, 1997, and in revised form, September 15, 1997)

Sonja I. Gringhuis ^§ , Lou F. M. H. de Leij ^§ , Gary A. Wayman ^¶ , Hiroshi Tokumitsu ^¶ and Edo Vellenga

From the Divisions of  Hematology and ^§ Clinical Immunology, Department of Internal Medicine, University of Groningen, 9713 GZ Groningen, The Netherlands and the ^¶ Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201

The CD5 receptor on T lymphocytes is involved in T cell activation and T-B cell interactions. In the present study, we have characterized the signaling pathways induced by anti-CD5 stimulation in human T lymphocytes. In T lymphocytes, anti-CD5 co-stimulation enhances the phytohemagglutinin/anti-CD28-induced interleukin-2 (IL-2) mRNA accumulation 1.6-fold and IL-2 protein secretion 2.2-fold, whereby the up-regulation is mediated at both the transcriptional and post-transcriptional level. The CD5 signaling pathway up-regulates the IL-2 gene expression by increasing the DNA binding and transactivation activity of activator protein 1 but affects none of the other transcription factors like nuclear factor of activated T cells, nuclear factor B, Oct, and CD28-responsive complex/nuclear factor of mitogen-activated T cells involved in the regulation of the IL-2 promoter activity. The CD5-induced increase of the activator protein 1 activity is mediated through the activation of calcium/calmodulin-dependent (CaM) kinase type IV, and is independent of the activation of mitogen-activated protein kinases Jun N-terminal kinase, extracellular signal-regulated kinase, and p38/Mpk2, and calcium/calmodul-independent kinase type II. The expression of a dominant negative mutant of CaM kinase IV in T lymphocytes transfected with an IL-2 promoter-driven reporter construct completely abrogates the response to CD5 stimulation, indicating that CaM kinase IV is essential to the CD5 signaling pathway. In addition, it is demonstrated that calcium/calmodulin-dependent kinase type IV is also involved in the stabilization of the IL-2 transcripts, which is observed after co-stimulation of phytohemagglutinin/anti-CD28 activated T lymphocytes with anti-CD5.

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