Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells

Accurate prediction of protein structures and interactions using a 3-track network

“…S8). A previously published cryoEM map of the IL-12 receptor complex indicated a similar topology to that of the IL-23 receptor, however, the resolution was not sufficient to observe the detailed interaction between IL-12Rβ2 and IL-12p35 (30). Such an understanding is important for dissecting the specific actions of IL-12 and IL-23 as well as generating inhibitors which block IL-12 without impacting IL-23 signaling.…”

Probing the Binding of Interleukin-23 to Individual Receptor Components and the IL23 Heteromeric Receptor Complex in Living Cells Using NanoBRET

“…The higher affinity of IL23-TMR for IL12Rb1 in live cells is also consistent with previous reports that cells expressing IL12Rb1 have a 2-to 5-nM affinity for the IL-12 cytokine (Chua et al, 1994). This observation is pertinent to the current study, given that IL-12 and IL-23 heteromers share the IL12p40 cytokine subunit and have both been shown to engage their receptors in a similar manner (Glassman et al, 2021).…”

“…Contrary to previous predictions based on the assembly of the closely related IL-6 receptor complex, the individual IL-23 receptor subunits appear to bind to distinct a and b chains of IL-23 (Schroder et al, 2015). Two recent studies have used X-ray crystallography to solve the structures of the IL-23:IL23R and IL-23:IL23R:IL12Rb1(D1) complexes, respectively, with the latter group also determining cryogenic electron microscopy structures for the extracellular domains of IL-12 and IL-23 cytokine:receptor complexes (Bloch et al, 2018;Glassman et al, 2021). This work and further mutational studies demonstrated that IL-12 engages its receptor in a similar way to IL-23, with IL12p40 binding IL12Rb1 and IL12p35 engaging IL12Rb2 (Esch et al, 2020;Glassman et al, 2021).…”

“…Two recent studies have used X-ray crystallography to solve the structures of the IL-23:IL23R and IL-23:IL23R:IL12Rb1(D1) complexes, respectively, with the latter group also determining cryogenic electron microscopy structures for the extracellular domains of IL-12 and IL-23 cytokine:receptor complexes (Bloch et al, 2018;Glassman et al, 2021). This work and further mutational studies demonstrated that IL-12 engages its receptor in a similar way to IL-23, with IL12p40 binding IL12Rb1 and IL12p35 engaging IL12Rb2 (Esch et al, 2020;Glassman et al, 2021). As part of the initial structural characterization of the IL23:IL23R complex, the affinity of IL-23 was measured for the purified extracellular domains of the IL-23 receptor using isothermal titration calorimetry (ITC).…”

Immunosuppressive Effects of Myeloid-Derived Suppressor Cells in Cancer and Immunotherapy

“…While some studies observed significant toxicities, others report high safety, suggesting that integrating safety mechanisms to control IL-12 secretion by CAR T-cells may be useful. Additionally, Glassman et al showed that IL-12 partial agonists could effectively promote anti-tumor immunity while eliminating NK cell-mediated toxicities [ 155 ]. Taken together, IL-12 has re-emerged as a potential approach to inhibit the suppressive effects of MDSCs and enhance the anti-tumor immunity of CAR T-cells.…”