Cutting Edge: Differential Fine-Tuning of IL-2– and IL-15–Dependent Functions by Targeting Their Common IL-2/15Rβ/γc Receptor

Abstract

Interleukin 2 and IL-15 are two closely related cytokines, displaying important functions in the immune system. They share the heterodimeric CD122/CD132 receptor to deliver their signals within target cells. Their specificity of action is conferred by their α receptor chains, IL-2Rα and IL-15Rα. By combining an increased affinity for CD122 and an impaired recruitment of CD132, we have generated an original molecule named IL-2Rβ/γ (CD122/CD132) inhibitor (BiG), targeting the CD122/CD132 receptor. BiG efficiently inhibited IL-15- and IL-2-dependent functions of primary cells, including CD8 T and NK cells, in vitro and in vivo. We also report a differential dynamic of action of these cytokines by highlighting a major role played by the IL-2Rα receptor. Interestingly, due to the presence of IL-2Rα, BiG had no impact on IL-2-dependent regulatory T cell proliferation. Thus, by acting as a fine switch in the immune system, BiG emphasizes the differential roles of these two cytokines.

CD122 blockade restores immunological tolerance in autoimmune type 1 diabetes via multiple mechanisms

“…Though via an entirely different design, this modified IL-15/IL-15Rα complex inhibited the activation and proliferation of conventional lymphocytes with negligible impact on Tregs (73), an outcome similar to what we have found in this study. Therefore, by modulating IL-2/IL-15R signaling using either engineered antibodies (e.g., ChMBC7) or modified cytokines (74,75), pathogenic immune responses can be abrogated without diminishing Treg function.…”

“…Recently, a molecule complex composed of a mutant IL-15 covalently linked to IL-15Rα was reported to exhibit an increased affinity for CD122 and an impaired recruitment of CD132 (73). Though via an entirely different design, this modified IL-15/IL-15Rα complex inhibited the activation and proliferation of conventional lymphocytes with negligible impact on Tregs (73), an outcome similar to what we have found in this study.…”

Simulation of Stimulation: Cytokine Dosage and Cell Cycle Crosstalk Driving Timing-Dependent T Cell Differentiation

“…The evidence presented here highlights a putative double role of p27 in the development and differentiation of CD4+ T cells: ( i ) during the initial immune response, p27 inhibits proliferation of T cells upon CD28 co-stimulation, and ( ii ) p27 inhibits development of memory T cells by promoting apoptosis. The underlying molecular pathways are not entirely understood; however, a few mechanisms have been suggested ( Jatzek et al, 2012 ): ( i ) an altered balance between the transcription factors T-bet, leading to T h 1 terminal differentiation, and Bcl-6, leading to development of T h 1 memory precursors ( Oestreich et al, 2012 ), and ( ii ) a p27-dependent downregulation of the IL-7 and IL-2/IL-15 receptors [CD127 and CD122 ( Meghnem et al, 2017 ), respectively], leading to a decreased expression of pro-survival/anti-apoptotic proteins, such as Bcl-2, that promote survival of memory T cells ( Xue and Zhao, 2012 ) ( Figure 4B ).…”

TPD7 inhibits the growth of cutaneous T cell lymphoma H9 cell through regulating IL‐2R signalling pathway

“…Interleukin‐2 (IL‐2), a 15.5 kD type 1 four α‐helical bundle cytokine, was first discovered in 1976s as a T cell growth factor present in supernatants of activated human T cells . It is well‐documented that IL‐2 exerts its biological activities through binding to three classes of cell surface IL‐2 receptors (IL‐2R), IL‐2Rα (CD25), IL‐2Rβ (CD122) and IL‐2Rγ (CD132) . Interestingly, IL‐2Rα subunit has no effect on signal transduction but primarily increases the affinity of ligand binding, while the β and γ subunits not only participate in ligand binding, but also exert crucial functions during the IL‐2/IL‐2R signal transduction through associated with the Janus kinases (JAK) .…”

“…4,5 It is well-documented that IL-2 exerts its biological activities through binding to three classes of cell surface IL-2 receptors (IL-2R), IL-2Rα (CD25), IL-2Rβ (CD122) and IL-2Rγ (CD132). 6,7 Interestingly, IL-2Rα subunit has no effect on signal transduction but primarily increases the affinity of ligand binding, while the β and γ subunits not only participate in ligand binding, but also exert crucial functions during the IL-2/IL-2R signal transduction through associated with the Janus kinases (JAK). 8 IL-2 binds with low affinity to IL-2Rα, while the βγ dimer binding IL-2 shows intermediate affinity and the highest affinity binding form is the αβγ trimeric complex.…”