ANTI-CD2 MONOCLONAL ANTIBODY-INDUCED RECEPTOR CHANGES - DOWN-MODULATION OF CELL-SURFACE CD2

Anti-CD2 mAbs suppress T cell immunity and prolong allograft survival in vivo while inducing the down-modulation of CD2 expression. Manipula tion of cell surface molecules may be important in inducing tolerance, so down-modulation of CD2 expression on T cells by anti-CD2 mAbs was further defined with an in vitro model. The anti-CD2 mAb 12-15 caused CD2 expression on purified splenic T cells to decrease from 83.4 to 22 .7% total positive cells while CD3, CD4, and CD8 expression remained u nchanged. The expression of other adhesion molecules, LFA-1 alpha (CD1 1a), LFA-1 beta (CD18), Pgp-1 (CD44), CD45, MEL-14 (L-selectin), and V LA-4 alpha (CD49d), were all increased as a result of anti-CD2 treatme nt, whereas CD25 (IL-2R), CD48 (CD2 ligand), and ICAM-1 (CD54) remaine d unchanged. Kinetics showed that CD2 down-modulation was persistent a nd at the same magnitude from day 1 through day 7 of culture. Anti-CD2 mAb could down modulate CD2 on both CD4 and CDS splenic lymphocyte su bsets, thymocytes, and the T cell lymphoma EL-4; and, non-T cells did not seem to participate in the process of modulation. Mechanistic stud ies of mAb action showed that, in addition to 12-15, other anti-CD2 mA bs could cause down-modulation of T cell CD2 expression in an epitope and isotype dependent fashion and that CD2 down-modulation correlated with inhibition of receptor-driven T cell stimulation. Intact antibody , including the Fc portion, was required to induce CD2 down-modulation , and additional experiments suggested an interaction with an Fc gamma R other than Fc gamma RII or Fc beta RIII. CD2 down-modulation did no t change with the addition of the cytokines IL-1, IL-2, IL-6, IL-10, T NF alpha, or TGF-beta 1. These results show that anti-CD2 mAbs signifi cantly and persistently downmodulate CD2 on various T cell subpopulati ons. The mAbs must interact with both the CD2 receptor and an Fc gamma R. CD2 down-modulation is accompanied by changes in the array of othe r T cell surface receptors that may contribute to mechanisms of anti-C D2-induced immunosuppression.