THE TUMOR-ASSOCIATED CELL-SURFACE ANTIGEN A6H IS COSTIMULATORY FOR HUMAN CD4(-CELLS() BUT NOT CD8(+) T)

The A6H monoclonal antibody (mAb) recognizes a 120000-140000 MW antige n that is expressed at similar densities on 85-90% of human CD4(+) and CD8(+) T cells and on renal cell carcinomas. The binding of the A6H m Ab induced a costimulatory signal in anti-CD3 activated T cells. In th e present report, we show that A6H costimulated cell proliferation and cytokine production in purified CD4(+) T cells. Unexpectedly, the CD8 (+) T-cell subpopulation failed to respond. CD4(+) T cells costimulate d with the A6H mAb upregulated CD80, CD86, CD71, interleukin-2 (IL-2)R alpha, IL-2R beta and IL-2R gamma, while no corresponding up-regulati on of these cell surface molecules was seen in CD8(+) T cells. In orde r to investigate the nature of the A6H mAb costimulus at the transcrip tional level we have examined induction of the transcription factors O CT-1, AP-1 and NF-kappa B which are known to be transcriptional regula tors of several cytokine and cytokine receptor genes, including the IL -2 and IL-2R genes. Co-ligation of the A6H antigen and the CD3 complex induced expression of the transcription factor AP-1 in CD4(+) T cells , whereas no increase in NF-kappa B and octamer-binding (Oct) proteins was seen compared to T cells stimulated with anti-CD3 alone. Furtherm ore, no induction of AP-1 was seen in A6H costimulated CD8(+) T cells. These results suggests that both proximal steps in CD8(+) T-cell acti vation as well as the later phases are unresponsive to A6H ligation. M olecular differences of the A6H molecule or distinct regulation of the A6H transduced AP-1 activation pathway may exist in CD4(+) and CD8(+) T cell subpopulations.