THE CA2+ CALMODULIN-DEPENDENT KINASE TYPE-IV IS INVOLVED IN THE CD5-MEDIATED SIGNALING PATHWAY IN HUMAN T-LYMPHOCYTES/

The CD5 receptor on T lymphocytes is involved in T cell activation and T-B cell interactions. In the present study, we have characterized th e signaling pathways induced by anti-CD5 stimulation in human T lympho cytes, In T lymphocytes, anti-CD5 co-stimulation enhances the phytohem agglutinin/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 i ncreasing the DNA binding and transactivation activity of activator pr otein 1 but affects none of the other transcription factors like nucle ar factor of activated T cells, nuclear factor kappa B, OCt, and CD28- responsive complex/nuclear factor of mitogen-activated T cells involve d in the regulation of the IL-2 promoter activity. The CD5-induced inc rease of the activator protein 1 activity is mediated through the acti vation of calcium/calmodulin-dependent (CaM) kinase type IV, and is in dependent 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 IL The expression of a d ominant negative mutant of CaM kinase IV in T Iymphocytes transfected with an IL-2 promoter-driven reporter construct completely abrogates t he response to CD5 stimulation, indicating that CaM kinase IV is essen tial to the CD5 signaling pathway, In addition, it is demonstrated tha t calciuml/calmodulin-dependent kinase type IV is also involved in the stabilization of the IL-2 transcripts, which is observed after co-sti mulation of phytohemagglutinin/anti-CD28 activated T lymphocytes with anti-CD5.