International Immunology, Vol. 12, No. 3, 253-261,
March 2000
© 2000 Japanese Society for Immunology
Selective induction of p38 mitogen-activated protein kinase activity following A6H co-stimulation in primary human CD4+ T cells
BMC Immunobiology, Department of Tumor Immunology, University of Lund, Sölvegatan 21, 223 62 Lund, Sweden
Correspondence to: T. Labuda
We have recently described the novel A6H antigen expressed on human peripheral blood T cells and on renal cell carcinoma cells. Cross-linking of the A6H antigen results in co-stimulation of human CD4+ T cells, characterized by induction of the transcription factor activator protein-1 (AP-1), proliferation and prominent IFN-
production, but low levels of IL-2. The proximal signaling events associated with A6H ligation include protein tyrosine kinase phosphorylation and association of p56 Lck, ZAP-70 and the TCR 
chain. In this study we show that A6H co-stimulation selectively induced activation of the p38 mitogen-activated protein kinase (MAPK) pathway, whereas no significant c-Jun N-terminal kinases (JNK) activity was observed. In contrast, CD28 co-stimulation resulted in both p38 and JNK MAPK activities. Human CD4+ T cells co-stimulated with A6H up-regulated AP-1 binding proteins reactive with a proximal AP-1 binding site in the human IFN- promoter and a consensus AP-1 binding site. Moreover, preincubation of the T cells with the specific p38 MAPK inhibitor SB203580 resulted in decreased AP-1 binding following A6H or CD28 co-stimulation. This suggests that the p38 MAPK pathway is required for induction of full AP-1 binding activity in human CD4+ T cells co-stimulated with A6H or CD28. Blocking the p38 MAPK pathway by SB203580 completely inhibited IFN- production from A6H co-stimulated T cells and radically reduced IFN- production from T cells co-stimulated with anti-CD28. In contrast, no significant inhibition of IL-2 production was seen after blocking of the p38 MAPK in either A6H or CD28 co-stimulated T cells. Since the p38 MAPK recently has been shown to be critically involved in regulation of IFN- production from Th1 cells, we propose that A6H co-stimulation induces a specific pathway, mediated via p38 and AP-1 activation, for induction of a Th1 profile in human CD4+ T cells.
Keywords: co-stimulatory molecules, human, signal transduction, T lymphocytes, transcription factors
Transmitting editor: H. Wigzell
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