The role of CD2/LFA-3 interaction in antigen- and mitogen-induced activation of human T cells

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Abstract
Binding of LFA-3 to the T cell surface receptor CD2 promotes intercellular adhesion and is costimulatory with anti-CD2 mAbs in ‘alternative pathway’ activation of T cells. Since all AC- dependent systems of T cell activation are inhibited by anti-LFA-3 mAb, it was asked whether in mltogen- and antigen-induced activation of human T cells, the function of CD2/LFA-3 interaction involves signalling beyond its function in promoting intercellular adhesion. In order to selectively block and reconstitute CD2/LFA-3 interaction while leaving other AC functions available, the response of unseparated PBMC to various T cell mitogens and to allogeneic cells was blocked by a newly developed mAb (G26) to human LFA-3. Addition of purified T11TS, the sheep form of LFA-3 that binds to human CD2 but is not recognized by mAb G26, restored the T cell response to PHA-P but not to ConA, surface aldehydes, anti-CD3 mAb, or allogeneic cells. In addition, purified resting human T cells which were unresponsive to stimulation by lectins or anti-CD3 mAbs were activated by PHA-P in the presence of purified T11TS, demonstrating that provision of LFA-3 is a sufficient accessory cell function in the activation of human T cells by this mitogen. Again, the responses to ConA, cell surface aldehydes, or soluble anti-CD3 mAb were not restored by T11TS. T cell activation by PHA-P, but not by the other polyclonal T-cell activators studied thus seems to be mechanistically similar to ‘alternative pathway’ activation induced by anti-CD2 mAb in that the costimulatory effect of LFA-3 is independent of its presence on an accessory cell membrane. The possibility was then investigated that T cell activation via the TcR required the coexpression of the ligands for CD2 and the TcR on the same cell membrane. Coating of sheep erythrocytes, which express T11TS, with anti-CD3 mAb yielded a strong mitogen for purified resting human T lymphocytes. Anti-CD3 coated rat RBC, which do not express a ligand for human CD2, were ineffective. Furthermore, simultaneous addition of anti-CD3 rat RBC and uncoated SRBC was not stimulatory, indicating a requirement for coexpression of the llgands for the TcR and CD2 on the same cell membrane. T cell activation by anti-CD3-SRBC, but not their adherence to T cells, was blocked by anti-T11TS mAb. Thus, the anti-CD3 mAb was sufficient to mediate adherence in this system and accordingly, binding of LFA-3 to CD2 was required for signalling rather than for cell – cell interaction.

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