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Interleukin-2 activity can be fine tuned with engineered receptor signaling clamps.

ABSTRACT: Interleukin-2 (IL-2) regulates lymphocyte function by signaling through heterodimerization of the IL-2R? and ?c receptor subunits. IL-2 is of considerable therapeutic interest, but harnessing its actions in a controllable manner remains a challenge. Previously, we have engineered an IL-2 "superkine" with enhanced affinity for IL-2R?. Here, we describe next-generation IL-2 variants that function as "receptor signaling clamps." They retained high affinity for IL-2R?, inhibiting binding of endogenous IL-2, but their interaction with ?c was weakened, attenuating IL-2R?-?c heterodimerization. These IL-2 analogs acted as partial agonists and differentially affected lymphocytes poised at distinct activation thresholds. Moreover, one variant, H9-RETR, antagonized IL-2 and IL-15 better than blocking antibodies against IL-2R? or IL-2R?. Furthermore, this mutein prolonged survival in a model of graft-versus-host disease and blocked spontaneous proliferation of smoldering adult T cell leukemia (ATL) T cells. This receptor-clamping approach might be a general mechanism-based strategy for engineering cytokine partial agonists for therapeutic immunomodulation.

SUBMITTER: Mitra S

PROVIDER: S-EPMC4560365 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Interleukin-2 activity can be fine tuned with engineered receptor signaling clamps.

Mitra Suman S Ring Aaron M AM Amarnath Shoba S Spangler Jamie B JB Li Peng P Ju Wei W Fischer Suzanne S Oh Jangsuk J Spolski Rosanne R Weiskopf Kipp K Kohrt Holbrook H Foley Jason E JE Rajagopalan Sumati S Long Eric O EO Fowler Daniel H DH Waldmann Thomas A TA Garcia K Christopher KC Leonard Warren J WJ

Immunity 20150501 5

Interleukin-2 (IL-2) regulates lymphocyte function by signaling through heterodimerization of the IL-2Rβ and γc receptor subunits. IL-2 is of considerable therapeutic interest, but harnessing its actions in a controllable manner remains a challenge. Previously, we have engineered an IL-2 "superkine" with enhanced affinity for IL-2Rβ. Here, we describe next-generation IL-2 variants that function as "receptor signaling clamps." They retained high affinity for IL-2Rβ, inhibiting binding of endogeno ...[more]

PMID: 25992859

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Project description:The quantitative prediction of transcriptional activity of genes using promoter sequence is fundamental to the engineering of biological systems for industrial purposes and understanding the natural variation in gene expression. To catalyze the development of new algorithms for this purpose, the Dialogue on Reverse Engineering Assessment and Methods (DREAM) organized a community challenge seeking predictive models of promoter activity given normalized promoter activity data for 90 ribosomal protein promoters driving expression of a fluorescent reporter gene. By developing an unbiased modeling approach that performs an iterative search for predictive DNA sequence features using the frequencies of various k-mers, inferred DNA mechanical properties and spatial positions of promoter sequences, we achieved the best performer status in this challenge. The specific predictive features used in the model included the frequency of the nucleotide G, the length of polymeric tracts of T and TA, the frequencies of 6 distinct trinucleotides and 12 tetranucleotides, and the predicted protein deformability of the DNA sequence. Our method accurately predicted the activity of 20 natural variants of ribosomal protein promoters (Spearman correlation r = 0.73) as compared to 33 laboratory-mutated variants of the promoters (r = 0.57) in a test set that was hidden from participants. Notably, our model differed substantially from the rest in 2 main ways: i) it did not explicitly utilize transcription factor binding information implying that subtle DNA sequence features are highly associated with gene expression, and ii) it was entirely based on features extracted exclusively from the 100 bp region upstream from the translational start site demonstrating that this region encodes much of the overall promoter activity. The findings from this study have important implications for the engineering of predictable gene expression systems and the evolution of gene expression in naturally occurring biological systems.

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Interleukin-2 activity can be fine tuned with engineered receptor signaling clamps.

Publications

Interleukin-2 activity can be fine tuned with engineered receptor signaling clamps.

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