We have investigated the etfects of monoclonal antibody (mAb) to the CD3ε protein on interactions between small, resting T cells and antigen-specific T helper clones. Highly purified, splenic T cells lacking Identifiable accessory cells do not proliferate in a thymidine uptake assay to anti-CD3 mAb, Con A, rIL-2, rIL-4, or irradiated T helper clones (both Th1 and Th2 However, the responding T cells proliferate significantly to the combined stimulus of Th2 clones and anti-CD3 antibody. Only the Th2 not the Th1, subpopulation of T helper cells has the abIlIty to induce a T cell response. The Th2 cell-dependent activation of small resting T cells does not require the external cross-linkage of the anti-CD3 mA.b via Fc receptor expressing cells or the secretion of lymphokines from the Th2 helper clones, but it is inhibitable by anti-LFA 1 antibody. Thus, Th2 clones provide a co-stimulalory signal which In conjunction with anti-CD3 mAb causes resting T cell proliferation in the absence of conventional accessory cells.