POTENT APOPTOTIC SIGNALING AND SUBSEQUENT UNRESPONSIVENESS INDUCED BYA SINGLE CD2 MAB (BTI-322) IN ACTIVATED HUMAN PERIPHERAL T-CELLS

Manipulation of CD2 molecules with CD2 mAb pairs has been shown to del iver apoptotic signals to activated mature T cells, We show that BTI-3 22, a CD2 mAb directed at a peculiar epitope of CD2, can trigger on it s own the apoptotic death of IL-2-activated peripheral T cells and of OKT3-stimulated T cells, contracting in this respect with a series of other mouse or rat CD2 mAb. F(ab')(2) fragments were as potent as the whole Ab, BTI-322-induced apoptosis proceeded in a few hours and was i ndependent of the Fas/Fas Ligand system, Less than 5 ng/ml of BTI-322, added at the begining of culture, were able to eliminate within 4 day s most CD3(+) cells from OKT3- and IL-2-stimulated lymphocytes, the on ly cells remaining being CD16(+)CD2(-)NK cells, T cell proliferative r esponses induced by a mitogenic CD3 mAb pair or by PHA-P (which mainly binds to CD2) were not inhibited by BTI-322. In this case, the apopto tic effect was successfully counteracted by simultaneous enhancement o f T cell divisions, Thus, the killing effect of BTI-322 was most effec tive when T cells were exclusively stimulated through the CD3/TCR comp lex. Apoptosis of the responding T cells may explain why T cells recov ered from a primary MLC performed in the presence of BTI-322 responded to third party cells but not to the primary stimulatory cells, These data constitute the rational basis for the use of BTI-322 for inducing tolerance in human allotransplantation.