Mitogenic pairs of CD2 mAb typically transduce activation/proliferation signals within T cells. However, complementary signal(s) provided by accessory cells are required to induce T cell proliferation. We show here that a particular combination of three CD2 mAb, D66 + GT2 + T11.1, leads to the proliferation of highly purified human T lymphocytes, without other complementary signal(s). The CD2 triplets was able to induce CD4+ and, to a lesser extent, CD8+ cells to proliferate. Interestingly, the so-called "naive" T cells (CD45RA+) were strongly stimulated, but more immature cells, such as thymocytes, were not. The proliferative response induced by the CD2 triplet was entirely mediated by the IL-2 autocrine pathway, as shown by the complete inhibition with anti-IL2 Ab. T cells stimulated with the CD2 triplet were also able to secrete TNF alpha. We found no evidence for an unusual secretion of cytokines that might explain the lack of requirement of complementary signal(s). As high as it was, the proliferation induced by the CD2 mAb triplet could be further increased by the addition of IL-1, and this proliferative fraction could be inhibited by antibodies against TNF alpha. The CD2 mAb triplet increased [Ca2+]i, while mitogenic CD2 mAb pairs needed the presence of a cross-linking agent. Thus, our data show that T cells can be activated to fully proliferate by this particular CD2 pathway, in the absence of accessory signal(s).