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Potent Apoptotic Signaling and Subsequent Unresponsiveness Induced by a Single CD2 mAb (BTI-322) in Activated Human Peripheral T Cells

Céline Dumont^*, Olivier Déas^*, Bertrand Mollereau^*, Chafika Hebib^*, Valérie Giovino-Barry, Alain Bernard, François Hirsch^*, Bernard Charpentier^* and Anna Senik^1,2,*

^* Centre National de Recherche Scientifique, UPR 420, Villejuif, France; Institut National de la Santé et de la Recherche Médicale, U343, Hôpital de l’Archet, Nice, France; and BioTransplant, Incorporated, Charlestown, MA.

Manipulation of CD2 molecules with CD2 mAb pairs has been shown to deliver apoptotic signals to activated mature T cells. We show that BTI-322, a CD2 mAb directed at a peculiar epitope of CD2, can trigger on its own the apoptotic death of IL-2-activated peripheral T cells and of OKT3-stimulated T cells, contrasting 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 independent 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 days most CD3⁺ cells from OKT3- and IL-2-stimulated lymphocytes, the only cells remaining being CD16⁺CD2^- NK cells. T cell proliferative responses induced by a mitogenic CD2 mAb pair or by PHA-P (which mainly binds to CD2) were not inhibited by BTI-322. In this case, the apoptotic effect was successfully counteracted by simultaneous enhancement of T cell divisions. Thus, the killing effect of BTI-322 was most effective when T cells were exclusively stimulated through the CD3/TCR complex. Apoptosis of the responding T cells may explain why T cells recovered 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.