Trends in Immunology
Volume 36, Issue 12, December 2015, Pages 763-777
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Review
Interleukin-2: Biology, Design and Application

https://doi.org/10.1016/j.it.2015.10.003Get rights and content

Trends

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.

Introduction

Discovered, isolated, and cloned between 1976 and 1983, IL-2 was the first immunotherapy demonstrating clinical efficacy in metastatic cancer 1, 2, 3, 4, 5. Despite these promising data, IL-2 immunotherapy has not been widely adopted for various reasons, including its difficult administration due to its short in vivo half-life (T½), its toxic adverse effects when administered at high doses (as needed for antitumor immunotherapy), and its ability to stimulate both cytotoxic effector T cells and regulatory T (Treg) cells [6]. While activation of Treg cells is an unwanted effect in anticancer IL-2 immunotherapy, as Treg cells can dampen effector T cell responses against tumor antigens, the property of IL-2 – even at low doses – to stimulate Treg cells could be harnessed for the treatment of Treg cell-deficient autoimmune and chronic inflammatory disorders [7].

The past 10 years rekindled an interest in IL-2 immunotherapy, which came from structural and biophysical insights into the complex formed by IL-2 with its IL-2 receptor (IL-2R) subunits [8] and the finding that IL-2 could be modified to selectively stimulate either cytotoxic effector T cells or Treg cells [9]; these studies have led to the generation of IL-2 formulations with improved and selective immune stimulatory capacities [10]. Furthermore, clinical trials using low-dose IL-2 have demonstrated IL-2's potential in expanding Treg cells and modulating immune pathologies 11, 12. Four recent publications exemplify this development and have motivated this review, in that they provide structural insight into the selective IL-2-mediated modulation of immune responses using IL-2/monoclonal antibody (mAb) complexes [13], highlight the possibility of using IL-2 muteins to antagonize, rather than stimulate, IL-2R-induced signals [14], and report novel data on the clinical use of low-dose IL-2 therapy in organ-specific and systemic autoimmune disease 15, 16.

To place these findings in context, we begin by providing an introduction into the biology of IL-2 and its receptors, followed by a discussion of IL-2/mAb complexes and IL-2 muteins, and end by summarizing the key concepts arising from these studies as well as indicating gaps in our current understanding.

Section snippets

The Biology of IL-2

IL-2 is a 15.5–16-kDa, four-α-helix-bundle cytokine (Figure 1) that exerts its actions via binding to various IL-2Rs, notably monomeric, dimeric, and trimeric IL-2Rs 6, 17, 18. Monomeric IL-2Rs, comprising IL-2Rα (CD25), are usually cell membrane associated but also exist in soluble form and bind IL-2 with a low Kd of ∼10−8 M. Interaction of IL-2 with CD25 alone does not induce a signal [19]; hence, isolated membrane-bound or soluble CD25 molecules might serve as scavenger or decoy receptors

IL-2/mAb Complexes

IL-2/mAb complexes (also termed IL-2 complexes or IL-2/anti-IL-2 mAb complexes) consist of IL-2 plus a particular anti-IL-2 mAb. The anti-IL-2 mAb can bind to and potentiate endogenous or recombinant IL-2 6, 9.

Two functionally distinct IL-2/mAb complexes are distinguished 6, 9, 47. Use of the anti-mouse IL-2 (mIL-2) mAb S4B6 (i.e., mAb clone S4B6-1 or other S4B6-like mAbs, including JES6-5H4 for mIL-2 and MAB602 for hIL-2) generates IL-2/mAb complexes that preferentially stimulate cells

IL-2 Muteins

An alternative approach to selective IL-2-mediated stimulation is the generation of IL-2 muteins. Initially, research in this area was driven by the search for IL-2 muteins with reduced toxic adverse effects. At that time, IL-2-induced toxic effects were thought to rely primarily on activated NK cells secreting proinflammatory cytokines, such as tumor necrosis factor-α, and vasoactive mediators, which in turn led to endothelial damage and VLS [69]. To this end, IL-2 muteins were generated with

Concluding Remarks

Taken together, the findings on IL-2/mAb complexes and IL-2 muteins suggest a mechanistic framework for IL-2-based selective immunotherapy, as exemplified by the two functionally different IL-2/mAb complexes (Figure 4). This concept hinges on the use of qualitatively different IL-2 variants, namely CD122-biased versus CD25-directed IL-2 formulations, rather than different IL-2 doses, such as high- versus low-dose IL-2 immunotherapy. IL-2/mAb complexes have served as a paradigm for IL-2-based

Acknowledgments

We thank the members of the Boyman laboratory for helpful discussions. This work was funded by Swiss National Science Foundation grant PP00P3-150751 and Swiss Cancer League grant KFS-3375-02-2014 (both to O.B.), as well as a Candoc fellowship from the University of Zurich (to J.W.).

The conceptual framework of IL-2-based selective immune modulation relies on biased IL-2 formulations. Do similar concepts exist for other cytokines, particularly γc cytokines?

Can the necessity of in vivo testing for

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