The effects of in vivo treatment with anti-Qa-2 mAbs on in vivo and in vitro parameters of T cell immunity have been examined. Two anti-Qa-2 mAbs of the same isotype and with similar avidities but directed against distinct epitopes of the same Qa-2 molecules were studied. mAb 1-1-2 was found to induce rapid T cell depletion, with maximal effect observed within 2-3 d, while administration of mAb 1-9-9 caused little or no depletion in the first few days, and reached maximal effect only by day 8. Surprisingly, administration of both antibodies resulted in a depletion pattern similar to that of the nondepleting antibody 1-9-9. Consistent with these effects on T cell depletion, treatment with 1-1-2 caused significant prolongation of survival of allogeneic skin grafts placed 1 d after antibody administration, while treatment with 1-9-9 or with the combination of both antibodies caused no prolongation. In an attempt to determine the mechanism of this phenomenon, we examined Qa-2 expression on the cell surface by flow microfluorometry after treatment with each of the two mAbs. Our data indicate that mAb 1-9-9 mediates significantly greater modulation of Qa-2 expression from the surface of peripheral T cells within 1 d than does mAb 1-1-2. Apparently, therefore, modulation occurs more rapidly than cell clearance, and the efficiency of T cell depletion and consequent immune suppression is correlated inversely with the ability of each mAb to cause modulation. The ability of 1-9-9 to cause Qa-2 modulation suggests that it may react with a determinant on this molecule of physiological relevance to the natural ligand interactions of Qa-2 antigens.