Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Facile Diversification of Interleukin-2 Pharmacology with Surrogate Agonists

ABSTRACT: Cytokines, such as interleukin-2, initiate signaling by dimerizing their receptors into orientations and proximities that induce intracellular signaling. We wished to explore a new pharmacological strategy for cytokine discovery based on variation of receptor dimer geometries using surrogate ligands, since natural cytokines are structurally limited as engineering scaffolds. Here, we report a structurally agonistic approach based on a modular, ‘plug and play’ class of ligands, that is amenable to high-throughout screening. We isolated nanobodies (Nb) and scFvs against human IL-2Rβ and γc, and generated a 40-member combinatorial matrix of tandem single-chain bispecific (IL-2Rβ:γc) molecules. We identified 28 surrogate IL-2 ligands exhibiting a wide range of agonist strengths and biased signaling properties, including cell-type bias for NK expansion and cytotoxity relative to T cells. Crystal structures of select Nb:receptor complexes validated that alternative receptor dimer geometries underly the functional diversification. This “cytokine med-chem” approach is generalizable to many dimeric cell surface receptor systems.

ORGANISM(S): Homo sapiens

PROVIDER: GSE183436 | GEO | 2022/04/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Mechanistic and structural insight into the functional dichotomy between interleukin-2 and interleukin-15

Project description:Interleukin-15 (IL-15) and IL-2 possess distinct immunological functions despite both signaling through IL-2Rβ and the common cytokine receptor γ-chain, γc, We find that in the IL-15/IL-15Rα/IL-2Rβ/γc quaternary complex structure, IL-15 heterodimerizes IL-2Rβ and γc identically to the IL-2/IL-2Rα/IL-2Rβ/γc complex, despite differing receptor-binding chemistries. IL-15Rα dramatically increases the affinity of IL-15 for IL-2Rβ, and this allostery is required for IL-15 trans-signaling versus IL-2 cis-signaling. Consistent with the identical IL-2Rβ/γc dimer geometry, IL-2 and IL-15 exhibited similar signaling properties in lymphocytes, with any differences resulting from disparate receptor affinities. Thus, IL-15 and IL-2 induce similar signals, and the cytokine-specificity of IL-2Rα versus IL-15Rα determines cellular responsiveness. These results provide important new insights for specific development of IL-15- versus IL-2-based immunotherapeutics. RNA-Seq is conducted in mouse CD8+ T cells, not treated or treated with IL2 or IL15 for indicated concentrations (1nM or 500nM) and times (4hr or 24hr).

2012-11-01 | E-GEOD-40350 | biostudies-arrayexpress

Mechanistic and structural insight into the functional dichotomy between interleukin-2 and interleukin-15

2012-11-01 | GSE40350 | GEO

Regulating Interleukin-2 activity with engineered receptor signaling clamps

Project description: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.

2015-06-16 | E-GEOD-64713 | biostudies-arrayexpress

Regulating Interleukin-2 activity with engineered receptor signaling clamps

2015-06-16 | GSE64713 | GEO

undefined

Project description:Reprogramming of flagellin receptor responses with surrogate ligands

| PRJEB60233 | ENA

Project description:Reprogramming of flagellin receptor responses with surrogate ligands

| PRJNA939365 | ENA

Expanding Hematopoietic Stem Cell pool through Fine tuning of Tpo receptor with diabodies.

Project description:Class I cytokine receptors such as Thrombopoietin receptor (MPL) are dimers, but it is unclear whether remodeling receptor dimer topology is a viable strategy to "tune" signaling output. We utilized diabodies (DA) as surrogate ligands in a prototypical dimeric receptor-ligand system, the cytokine Thrombopoietin (TPO) and its receptor (TpoR), to dimerize TpoR ectodomains in non-native architectures. Diabody-induced signaling amplitudes varied from full to minimal agonism. Here we describe a single-cell transcriptome analysis of 659 human Hematopoietic Stem Cells cultured with different DA. We find several difference between differentiation and activation of signaling pathways compared to TPO.

2021-02-01 | GSE115235 | GEO

Characterization of receptor-associated protein complex assembly in Interleukin (IL)-2- and IL-15-activated T-lymphocytes

Project description:Despite extensive investigation, it remains a paradox that IL-2 and IL-15 can differentially modulate the immune response using the same signaling receptors. In our previous work, we dissected the phosphotyrosine-driven signaling cascades triggered by both cytokines in Kit225 T-cells unveiling subtle differences that may contribute to their functional dichotomy. In the present study, we aimed to decipher the receptor complex assembly in IL-2- and IL-15-activated T-lymphocytes that is fine tune orchestrated by site-specific phosphorylation events. Comparing the cytokine-induced interactome of the interleukin receptor beta and gamma subunits shared by the two cytokines, we defined the components of the early IL-2 and IL-15 receptor-associated complex discovering novel constituents such as FAM59A and SOCS2. Additionally, phosphopeptide-directed analysis allowed us to detect several cytokine-dependent and –independent phosphorylation events within the activated receptor complex including novel phosphorylated sites located in the cytoplasmic region of IL-2Rβ. We proved that the distinct phosphorylations induced by the cytokines serve for recruiting different types of effectors to the initial receptor/ligand complex. Whereas IL-2Rβ pS431 binds to clathrins, which are involved in the receptor internalization and subsequent signal attenuation, IL-2Rγ pY325 and pY357 attract phosphatases, adaptor proteins, kinases as well as the newly identified member of the interleukin receptor complex SOCS2. Overall our study sheds new light into the initial molecular mechanisms triggered by IL-2 and IL-15 and constitutes a further step towards a better understanding of the early signaling aspects of the two closely-related cytokines in T-lymphocytes.

2016-08-08 | PXD002386 | Pride

IL-2Rβ- and CD103-dependent genes in regulatory T cells in the gut mucosa

Project description:This study determined the genes that are differentially expressed when regulatory T cells (Tregs) were isolated from the lamina propria of the small and large intestine from mice with impaired IL-2Rβ signaling (designated Y3) or impaired IL-2Rβ signaling and lack of CD103 expression (designated Y3/CD103-/-) when compared to Tregs from WT mice. 204 unique annotated mRNAs were differentially expressed by ≥1.5 fold between these 3 groups (Fig. 6B). Very few mRNAs were uniquely up or down regulated in relationship to impaired IL-2Rβ signaling or the combination of impaired IL-2Rβ signaling and lack of CD103 expression. Thus, lack of CD103 does not obviously regulated signaling in Tregs in the gut mucosa and most differentially expressed genes were due to impaired IL_2Rβ signaling. Gene enrichment analysis of these differentially expressed genes identified 4 major enrichment groups (EG) are: EG1, Cytokine-cytokine receptor interaction and the JAK-STAT signaling pathway; EG2, regulation of lymphocyte activation and proliferation; EG3, regulation of cell death and the caspase pathway in apoptosis; and EG4, transcription.

2015-01-06 | GSE56438 | GEO

IL-2Rβ- and CD103-dependent genes in regulatory T cells in the gut mucosa

2015-01-06 | E-GEOD-56438 | biostudies-arrayexpress