Overall, there is stronger molecular evidence that IL-2 is important for Th2 generation 23 than for Th1 cells. This leaves open the possibility that a direct Th2-skewing effect of IL-2 may also contribute to the protective function of IL-2-antibody complexes in myasthenia gravis. Although recent interest in IL-2 for the treatment of autoimmunity stems from IL-2′s role in the maintenance of Treg, the activities of this growth factor on effector cells must be taken into account when evaluating IL-2′s therapeutic potential. Indeed, in a study using IL-2 to prevent diabetes in selleckchem the NOD mouse 16, it was found that high doses
of IL-2 complexes expanded effector cells and led to accelerated onset of diabetes. To the contrary, low doses of IL-2 prevented the onset of diabetes by restoring functional Treg in the pancreas. The detrimental outcome this website of IL-2 treatment is likely due to the induction of strong effector and memory responses in the autoimmune-prone mice. Recent studies have demonstrated a prominent role for IL-2 in
the generation of CD4+ and CD8+ memory T cells 24, 25. This function is obviously unwanted when treating autoimmune disease but the current body of evidence suggests that careful determination of IL-2 complex doses and timing to specifically target Treg provides a rationale to circumvent these problems 16. It may be that lower doses of IL-2 complexes favor Treg function, whereas higher doses will boost effector/memory cell formation. The high levels of CD25 on Treg compared with naïve and effector cells may explain this differential sensitivity, allowing Treg to outcompete effector cells for capturing
environmental IL-2. It is likely that assays for IL-2 action, such as phospho-flow analyses 14, will help us better define IL-2′s targets under different conditions of exposure. In addition, combination therapy, such as IL-2 to promote Treg numbers and function and mTOR inhibitors to block the generation of effector T cells, may prove to be beneficial in immunological disorders. IL-2 is one of the first cytokines heptaminol discovered and it was thought that IL-2′s function is well understood. Studies in the past 10 years have led to new insights into the biology of IL-2 and an astonishing re-evaluation of the dogma. It is especially remarkable that almost two decades ago this cytokine was being tested for its ability to boost immune responses and now it is being considered as a therapy to inhibit immune responses. The development of better assays to define cytokine actions in vivo and rational strategies to optimize the actions of cytokines may help to realize the potential of IL-2 as an immunotherapeutic agent. Supported by NIH grants RO1 AI073656 and P01 AI35297 (to A. K. A.), and JDRF grant 32-2008-354 (to H. D.). Conflict of interest: The authors declare no financial or commercial conflict of interest. See accompanying article: http://dx.doi.org/10.1002/eji.