Interleukin-2: Biology, Design and Application

Interleukin-2 (IL-2) exerts immunosuppressive and immunostimulatory effects by activating regulatory T (Treg) versus cytotoxic effector cells. These IL-2 effects hinge on different IL-2 receptor (IL-2R) expression patterns: CD8+ T and natural killer cells carry high levels of dimeric IL-2Rs comprising IL-2Rβ (CD122) and IL-2Rγ (γc); Treg cells express high IL-2Rα (CD25) levels along with intermediate levels of CD122 and γc. Selective IL-2 formulations, such as IL-2 complexes and IL-2 muteins, preferentially stimulate cells expressing high CD25 versus high CD122 levels, and recent studies extend these concepts to also include muteins that inhibit IL-2R-induced responses. These data converge into a framework of IL-2-mediated selective immune modulation where CD25-biased IL-2 formulations primarily expand Treg cells and CD122-directed IL-2 formulations stimulate cytotoxic effector cells. Interleukin-2 (IL-2) exerts crucial functions during immune homeostasis via its effects on regulatory T (Treg) cells, and the optimizing and fine-tuning of effector lymphocyte responses. Thus, somewhat paradoxically, low doses of recombinant IL-2 have been used for Treg cell-based immunosuppressive strategies against immune pathologies, while high-dose IL-2 has shown some success in stimulating anti-tumor immune responses. Recent studies of the functional, biophysical and structural characteristics of IL-2 have led to the generation of IL-2 formulations, including IL-2/mAb complexes and IL-2 variants (muteins) that selectively enhance IL-2's immune stimulatory versus inhibitory properties. Here, we review these findings, placing new mechanistic insights into improved next-generation IL-2 formulations within the broader context of IL-2 biology. We conclude by integrating these findings into a framework for understanding IL-2-mediated selective immune modulation. Interleukin-2 (IL-2) exerts crucial functions during immune homeostasis via its effects on regulatory T (Treg) cells, and the optimizing and fine-tuning of effector lymphocyte responses. Thus, somewhat paradoxically, low doses of recombinant IL-2 have been used for Treg cell-based immunosuppressive strategies against immune pathologies, while high-dose IL-2 has shown some success in stimulating anti-tumor immune responses. Recent studies of the functional, biophysical and structural characteristics of IL-2 have led to the generation of IL-2 formulations, including IL-2/mAb complexes and IL-2 variants (muteins) that selectively enhance IL-2's immune stimulatory versus inhibitory properties. Here, we review these findings, placing new mechanistic insights into improved next-generation IL-2 formulations within the broader context of IL-2 biology. We conclude by integrating these findings into a framework for understanding IL-2-mediated selective immune modulation.