7zmz
From Proteopedia
Engineered Interleukin 2 bound to CD25 receptor
Structural highlights
DiseaseIL2_HUMAN Note=A chromosomal aberration involving IL2 is found in a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(4;16)(q26;p13) with involves TNFRSF17. FunctionIL2_HUMAN Produced by T-cells in response to antigenic or mitogenic stimulation, this protein is required for T-cell proliferation and other activities crucial to regulation of the immune response. Can stimulate B-cells, monocytes, lymphokine-activated killer cells, natural killer cells, and glioma cells. Publication Abstract from PubMedCytokines 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-2Ralpha 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. IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein.,Gaggero S, Martinez-Fabregas J, Cozzani A, Fyfe PK, Leprohon M, Yang J, Thomasen FE, Winkelmann H, Magnez R, Conti AG, Wilmes S, Pohler E, van Gijsel Bonnello M, Thuru X, Quesnel B, Soncin F, Piehler J, Lindorff-Larsen K, Roychoudhuri R, Moraga I, Mitra S Sci Immunol. 2022 Dec 9;7(78):eade5686. doi: 10.1126/sciimmunol.ade5686. Epub , 2022 Dec 2. PMID:36459543[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations 14 reviews cite this structure No citations found See AlsoReferences
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