Despite an attenuated proliferative response in human cord blood mononuclear cells (CBMCs) to activation of its TCR in vitro, the neonate is capable of mounting a mature T(h)1-type response to BCG vaccination. We hypothesized that in the context of other innate triggers, activation of the TCR can be restored. In order to test this hypothesis, we analyzed CBMC response to LPS, with LPS serving as a surrogate activator of the innate system. We performed proliferative assays on 34 maternal-neonatal pairs of PBMCs and CBMCs, respectively. In all, 30/34 (88%) of CBMCs proliferated in response to LPS (10 microg ml(-1), P < 2.7 x 10(-7)), in contrast to only 10/32 (31%) of their respective maternally derived PBMCs, despite having a comparatively greater response to PHA than did their CBMC counterparts (P < 0.0002). LPS synergized with immobilized anti-human CD3epsilon mAb (1.25-10 microg ml(-1)) to augment the proliferative response in CBMCs but failed to do so in maternally derived PBMCs. LPS responsiveness and its synergy with activation of the TCR in CBMCs were independent of accessory cells. These results are the first evidence that LPS and anti-CD3 mAb are synergistic, demonstrating a critical link between the innate and adaptive immune systems.