Cross-linking of the CAMPATH-1 antigen (CD52) triggers activation of normal human T lymphocytes

The CAMPATH-1 (CD52) antigen is a 21–28 kDa glycopeptidewhich is highly expressed on lymphocytes and macrophages andis coupled to the membrane by a glycosylphosphatidylinositol(GPI) anchoring structure. The function of this molecule isunknown. However, it is an extremely good target for complement-mediatedattack and antibody-mediated cellular cytotoxicity. The humanizedCAMPATH-1H antibody, which is directed against CD52, is veryefficient at mediating lymphocyte depletion in vivo, and iscurrently being used in clinical trials for lymphoid malignancyand rheumatoid arthritis. It is therefore important to examinethe functional effects of this antibody on different lymphocytesub-populations. Because several other GPI-linked moleculesexpressed on the surface of T lymphocytes are capable of signaltransductlon resulting in cell proliferation, we have investigatedwhether the CAMPATH-1 antigen can also mediate these effects.In the presence of phorbol esters and cross-linking anti-lgantibodies, mAbs specific for CD52 induced proliferation andlymphokine production in highly purified resting CD4⁺ and CD8⁺T lymphocytes. The ret lgG2c YTH 361.10 anti-CD52 antibody,however, was able to activate resting CD4⁺ and CD8⁺ T cellsdirectly without cross-linking or phorbol myristate acetatein the absence of Fc-bearlng cells. Anti-CD52 antibodies alsoaugmented the anti-CD3 mediated proliferatlve response of CD4⁺and CD8⁺ T cells when the two antibodies were co-immobilizedonto the same surface or cross-linked in solution by the samesecond antibody. Both CD4⁺CD45RA and CD4⁺CD45RO T cells werestimulated to proliferate by anti-CD52 antibodies in the presenceof appropriate co-stimulatory factors. Antl-CD52 mAbs did not,however, synerglze with anti-CD2 or CD28 mAb to induce CD4⁺T cell proliferation. The activation of CD4⁺ T cells by antl-CD52antibodies was inhibited by cyclosporin A, suggesting a rolefor the calcineurin-dependent signal transduction pathways.Although CD52 could transduce a signal In T cells, anti-CD52antibodies did not inhibit antigen-specific or polyclonal Tcell responses, suggesting this molecule does not play an essentialco-stimulatory role in normal T cell activation.