Cytokines and mechanisms of lymphocyte activation

Specific upstream segments of several cytokine genes are required for induction in T lymphocytes and work only in T lymphocytes. Control is exerted at the transcriptional level, but the relative instability of certain cytokine mRNAs (a property imparted by specific AU-rich segments in their 3' untranslated regions) also makes them susceptible to regulation at the post-transcriptional level. One consequence is that upon removal of the inductive signal, the level of mRNA falls rapidly and synthesis of the protein stops. CS is therefore able to exert an immunosuppressive effect by blocking the transcription of several cytokines. Although an enormous amount of detailed molecular and cellular information regarding cytokine biology has accumulated in the past decade, there is clearly much more to be learned. Even the types of answers required are in some cases not yet understood. For example, there is a paradox of timing in the cytokine response events compared with the overall cellular response. The changes in effector levels (Ca²⁺, PIs, cAMP, c-oncogenes) are transient, rising and falling in minutes. However, the cellular responses continue for many hours or days. IL-2 mRNA synthesis rapidly comes to a halt when the inducing ligand is removed from the exterior of the T cell, indicating that a signal for transcription was being continuously delivered. We presently have no candidate for this role, since the levels of known membrane-related signaling molecules rise only transiently at the time the inducing ligand is added. Another important conceptual development, one which will undoubtedly have profound importance for any pharmacologic applications of cytokines, is the question of parallel versus serial signaling when cytokines synergize with each other or with other stimulatory molecules such as antigen. If two cytokines induce the same proximal molecular response, one will usually suffice, given at a high enough level, to drive the response of the cell. But if the signals imparted are different, it is possible to drive the effect synergistically with lower concentrations of each cytokine, thereby reducing side effects. This kind of approach may be necessary in second generation applications to cancer immunotherapy with IL-2, for example, which have been plagued by toxic side-effects at the high doses required. Synergy may also need to be considered in understanding the basis of inflammatory responses driven by cytokines. As described here, the effects of IL-2 plus and IL-4 in the same reactive cellular complex can have a profound effect on the magnitude of response.