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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography	IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein Silvia Gaggero , Jonathan Martinez-Fabregas , Adeline Cozzani , Paul K. Fyfe , Malo Leprohon , Jie Yang , F. Emil Thomasen , Hauke Winkelmann , Romain Magnez , Alberto G. Conti , Stephan Wilmes , Elizabeth Pohler , Manuel Van Gijsel Bonnello , Xavier Thuru , Bruno Quesnel , Fabrice Soncin , Jacob Piehler , Kresten Lindorff-Larsen , Rahul Roychoudhuri , Ignacio Moraga , Suman Mitra Science Immunology 7 DOI: 10.1126/sciimmunol.ade5686 Show Abstract ▼ Abstract: Cytokines interact with their receptors in the extracellular space to control immune responses. How the physicochemical properties of the extracellular space influence cytokine signaling is incompletely elucidated. Here, we show that the activity of interleukin-2 (IL-2), a cytokine critical to T cell immunity, is profoundly affected by pH, limiting IL-2 signaling within the acidic environment of tumors. Generation of lactic acid by tumors limits STAT5 activation, effector differentiation, and antitumor immunity by CD8+ T cells and renders high-dose IL-2 therapy poorly effective. Directed evolution enabled selection of a pH-selective IL-2 mutein (Switch-2). Switch-2 binds the IL-2 receptor subunit IL-2Rα with higher affinity, triggers STAT5 activation, and drives CD8+ T cell effector function more potently at acidic pH than at neutral pH. Consequently, high-dose Switch-2 therapy induces potent immune activation and tumor rejection with reduced on-target toxicity in normal tissues. Last, we show that sensitivity to pH is a generalizable property of a diverse range of cytokines with broad relevance to immunity and immunotherapy in healthy and diseased tissues.	Dec 2022
Krios II-Titan Krios II at Diamond	Structural insights into the assembly and activation of the IL ‐27 signaling complex Yibo Jin , Paul K. Fyfe , Scott Gardner , Stephan Wilmes , Doryen Bubeck , Ignacio Moraga Embo Reports DOI: 10.15252/embr.202255450 Diamond Proposal Number(s): [25127] Open Access Show Abstract ▼ Abstract: Interleukin 27 (IL-27) is a heterodimeric cytokine that elicits potent immunosuppressive responses. Comprised of EBI3 and p28 subunits, IL-27 binds GP130 and IL-27Rα receptor chains to activate the JAK/STAT signaling cascade. However, how these receptors recognize IL-27 and form a complex capable of phosphorylating JAK proteins remains unclear. Here, we used cryo electron microscopy (cryoEM) and AlphaFold modeling to solve the structure of the IL-27 receptor recognition complex. Our data show how IL-27 serves as a bridge connecting IL-27Rα (domains 1–2) with GP130 (domains 1–3) to initiate signaling. While both receptors contact the p28 component of the heterodimeric cytokine, EBI3 stabilizes the complex by binding a positively charged surface of IL-27Rα and Domain 1 of GP130. We find that assembly of the IL-27 receptor recognition complex is distinct from both IL-12 and IL-6 cytokine families and provides a mechanistic blueprint for tuning IL-27 pleiotropic actions.	Aug 2022

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