Second signal for T lymphocyte activation: multiple targets for pharmacological modulation.

Complete T cell activation requires at least two signals. The first is delivered through the antigen-specific T cell receptor, whereas the second is generated by cognate interactions through adhesion molecules of T cells and antigen-presenting cells and/or by cytokines produced by antigen-presenting cells. The delivery of the two signals results in gene transcription, cytokine secretion, expression of new cell surface molecules including cytokine receptors, and cellular proliferation. Reference immunosuppressive agents were shown to act at different subsequent stages of T cell activation and proliferation. Among immunostimulating compounds, those which can enhance T cell responses are likely to modulate or replace the second signal in T cell activation, or alternatively, to act at later stages such as cytokine secretion, cytokine receptor expression or response to cytokine signals. For the purpose of in vitro evaluation of the activity of immunomodulators on the second signal of T cell activation, we devised a model of accessory cell depletion and reconstitution. This model allows the capacity of a given compound to enhance surface adhesion molecule expression or to trigger monocyte cytokine synthesis to be tested, and these effects to be assessed on T cell proliferation.