CD38 stimulation lowers the activation threshold and enhances the alloreactivity of cord blood T cells by activating the phosphatidylinositol 3-kinase pathway and inducing CD73 expression

We have recently described in cord blood T cells (CBTC) a novel pathway lin king CD38 and CD73, two signal transducers with ecto-enzyme activity. The a im of this study was 2-fold: first, to characterize the mechanisms by which CD38 regulates CD73 expression; and second, to determine whether surface-i nduced CD73 modulates CBTC responses. A marked increase in CD73 expression was observed in CD38(+) cells after incubation with the appropriate CD38 mA bs. The induction of CD73 was blocked by wortmannin, a specific inhibitor o f phosphatidylinositol 3-kinase (PI3-K), CD38 stimulation induced tyrosine phosphorylation of the p85 regulatory subunit of PI3-K and its association with other tyrosine-phosphorylated proteins. Surface-induced CD73 was as ef ficient in delivering activatory signals as the CD73 constitutively express ed on adult T cells. Highly CBTC, totally unresponsive to mitogenic concent rations of plastic-immobilized CD3 mAb, proliferated vigorously when expose d to the combination of plastic-immobilized CD3 and CD73 mAbs, The reactivi ty to allogeneic irradiated PBMC was also significantly enhanced by CD38 st imulation and was dependent on CD73 expression. Thus, CD38 stimulation lowe rs the activation threshold of CBTC by the CD3/TCR complex and enhances the ir reactivity to allogeneic cells via activation of the PB-kinase pathway a nd CD73 expression.