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Calibration of cell-intrinsic Interleukin-2 response thresholds guides design of a regulatory T cell biased agonist

ABSTRACT: Interleukin-2 (IL-2) is a pleotropic cytokine that mediates both pro- and anti-inflammatory functions. Immune cells natural differ in their sensitivity to IL-2 due to cell-type and activation-state dependent expression of receptors and signaling pathway components. To probe differences in IL-2 signaling across cell types, we created through structure-based design, and then profiled, a series of IL-2 variants with the capacity to titrate signal strength in fine increments. One of these partial agonists, IL-2-REH, specifically expanded FoxP3+ regulatory T cells (Tregs) with reduced activity on CD8+ T cells due to cell-type intrinsic differences in IL-2 signaling. IL-2-REH elicited cell-type dependent differences in gene expression and provided therapeutic benefit in an in vivo model of mouse Colitis. Our findings show that cytokine partial agonists can be used to calibrate intrinsic differences in response thresholds across responding cell types to narrow pleiotropic actions, which may be generalizable to other cytokine and growth factor systems.

ORGANISM(S): Mus musculus

PROVIDER: GSE162928 | GEO | 2021/05/12

REPOSITORIES: GEO

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Regulating Interleukin-2 activity with engineered receptor signaling clamps

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

Regulating Interleukin-2 activity with engineered receptor signaling clamps

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Calibration array

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2010-05-16 | E-GEOD-13042 | biostudies-arrayexpress

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2010-06-21 | E-GEOD-14717 | biostudies-arrayexpress

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2008-11-07 | GSE13042 | GEO

Transcription profiling of human dendritic cells to identify a combinatorial code by which DCs discriminate pathogens and provide (suggest) a rationale to design adjuvants for TH1 responses.

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2007-09-14 | E-GEOD-2706 | biostudies-arrayexpress

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Project description:We investigated whether exogenous supplies of different IL-2R agonists (IL-2wt, IL-2nα or IL-2α-bias) at the concentration of 3 mg/g body weight could rescue the transcriptional signatures of dysfunctional T cells in large tumors, or allow them to regain sensitivity to αPD-1 antibody. Remarkably, after transient stimulation by IL-2wt, large tumors fully restored the effector/activation signatures observed in small tumors, such as upregulation of effector genes (Gzma, Gzmb, Gzmk and Ifng), T cell activation/exhaustion genes (Ctla4, Pdcd1, Lag3 and Havcr2), inflammatory cytokine/cytokine receptors (Il2ra, Il2rb, Il2rg and Il21r), and chemokines (Cxcl9, Cxcl10 and Ccl19) (Fig.7d). Surprisingly, although IL-2α-bias had >10-fold weaker in vitro activity than IL-2wt, and could only activate the small fraction of CD25-upregulated CD8+Teff cells, the transcriptional profiles were indistinguishable between IL-2wt and IL-2α-bias treated large tumors. In stark contrast, IL-2nα treatment showed no meaningful transcriptional changes in large tumors compared to untreated control. These results once again demonstrate the critical role of CD25 in transmitting IL-2 signaling to reprogram the tumor immune microenvironment.

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