Transcriptomics,Genomics

Dataset Information

298

Regulating Interleukin-2 activity with engineered receptor signaling clamps


ABSTRACT: Interleukin-2 (IL-2) is a pleiotropic cytokine that regulates lymphocyte function by signaling through heterodimerization of the IL-2Rβ and γc receptor subunits. Previously, we engineered an IL-2 “superkine” (H9) with enhanced affinity for IL-2Rβ. Here, we describe next-generation IL-2 variants that function as “receptor signaling clamps.” They retain high-affinity for IL-2Rβ, thereby inhibiting binding of endogenous IL-2, but their engagement of γc is weakened, thereby attenuating IL-2Rβ-γc heterodimerization. These IL-2 analogues act as partial agonists and can differentially affect lymphocytes poised at distinct activation thresholds. Moreover, one of these variants potently antagonized IL-2 and IL-15 signaling and function better than blocking antibodies against IL-2Rα or IL-2Rβ. 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 ex vivo. This receptor-clamping approach may be a general mechanism-based strategy for engineering cytokine partial agonists for therapeutic immunomodulation. Genome-wide transcription factors binding of STAT5 and mRNA-Sequencing of gene expression profiles in human pre-activated CD8+ T cells.

ORGANISM(S): Homo sapiens  

SUBMITTER: Suzanne Fischer   Shoba Amarnath  Holbrook Kohrt  Sumati Rajagopalan  Wei Ju  Daniel H Fowler  Peng Li  Aaron M Ring  Jamie B Spangler  Jangsuk Oh  Warren J Leonard  Rosanne Spolski  Kipp Weiskopf  K.Christopher Garcia  Suman Mitra  Eric O Long  Thomas A Waldmann  Jason E Foley 

PROVIDER: E-GEOD-64713 | ArrayExpress | 2015-06-16

SECONDARY ACCESSION(S): SRP051736GSE64713PRJNA271704

REPOSITORIES: GEO, ArrayExpress, ENA

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Publications


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]

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