Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits

Carly E Whyte; Kailash Singh; Oliver T Burton; Meryem Aloulou; Lubna Kouser; Rafael Valente Veiga; Amy Dashwood; Hanneke Okkenhaug; Samira Benadda; Alena Moudra; Orian Bricard; Stephanie Lienart; Pascal Bielefeld; Carlos P Roca; Francisco José Naranjo-Galindo; Félix Lombard-Vadnais; Steffie Junius; David Bending; Tino Hochepied; Timotheus Y F Halim; Susan Schlenner; Sylvie Lesage; James Dooley; Adrian Liston

doi:10.1084/jem.20212391

Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits

Carly E Whyte, Kailash Singh, Oliver T Burton, Meryem Aloulou, Lubna Kouser, Rafael Valente Veiga, Amy Dashwood, Hanneke Okkenhaug, Samira Benadda, Alena Moudra, Orian Bricard, Stephanie Lienart, Pascal Bielefeld, Carlos P Roca, Francisco José Naranjo-Galindo, Félix Lombard-Vadnais, Steffie Junius, David Bending, Tino Hochepied, Timotheus Y F HalimSusan Schlenner, Sylvie Lesage, James Dooley, Adrian Liston

Immunology and Immunotherapy

Research output: Contribution to journal › Article › peer-review

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Abstract

Interleukin 2 (IL-2) is a key homeostatic cytokine, with therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical use has been hampered by pleiotropic functionality and widespread receptor expression, with unexpected adverse events. Here, we developed a novel mouse strain to divert IL-2 production, allowing identification of contextual outcomes. Network analysis identified priority access for Tregs and a competitive fitness cost of IL-2 production among both Tregs and conventional CD4 T cells. CD8 T and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified Tregs, whereas IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8⁺ Tregs and ILC2 cells, the latter driving a downstream, IL-5-mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain adverse effects observed during clinical trials. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability.

Original language	English
Article number	e20212391
Number of pages	30
Journal	The Journal of Experimental Medicine
Volume	219
Issue number	7
Early online date	14 Jun 2022
DOIs	https://doi.org/10.1084/jem.20212391
Publication status	Published - 4 Jul 2022

Bibliographical note

Keywords

Animals
Immunity, Innate
Interleukin-2/biosynthesis
Killer Cells, Natural/immunology
Mice
T-Lymphocytes, Regulatory/immunology

Access to Document

10.1084/jem.20212391Licence: Creative Commons: Attribution (CC BY)

WhyteC2022ContextFinal published version, 9.28 MBLicence: Creative Commons: Attribution (CC BY)

Negative feedback control of T cells in tolerance and cancer - from pathways to biomarkers
Bending, D. (Principal Investigator)
Medical Research Council
1/02/21 → 31/01/27
Project: Research Councils

Cite this

Whyte, C. E., Singh, K., Burton, O. T., Aloulou, M., Kouser, L., Veiga, R. V., Dashwood, A., Okkenhaug, H., Benadda, S., Moudra, A., Bricard, O., Lienart, S., Bielefeld, P., Roca, C. P., Naranjo-Galindo, F. J., Lombard-Vadnais, F., Junius, S., Bending, D., Hochepied, T., ... Liston, A. (2022). Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits. The Journal of Experimental Medicine, 219(7), Article e20212391. https://doi.org/10.1084/jem.20212391

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abstract = "Interleukin 2 (IL-2) is a key homeostatic cytokine, with therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical use has been hampered by pleiotropic functionality and widespread receptor expression, with unexpected adverse events. Here, we developed a novel mouse strain to divert IL-2 production, allowing identification of contextual outcomes. Network analysis identified priority access for Tregs and a competitive fitness cost of IL-2 production among both Tregs and conventional CD4 T cells. CD8 T and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified Tregs, whereas IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8+ Tregs and ILC2 cells, the latter driving a downstream, IL-5-mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain adverse effects observed during clinical trials. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability.",

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Whyte, CE, Singh, K, Burton, OT, Aloulou, M, Kouser, L, Veiga, RV, Dashwood, A, Okkenhaug, H, Benadda, S, Moudra, A, Bricard, O, Lienart, S, Bielefeld, P, Roca, CP, Naranjo-Galindo, FJ, Lombard-Vadnais, F, Junius, S, Bending, D, Hochepied, T, Halim, TYF, Schlenner, S, Lesage, S, Dooley, J & Liston, A 2022, 'Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits', The Journal of Experimental Medicine, vol. 219, no. 7, e20212391. https://doi.org/10.1084/jem.20212391

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T1 - Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits

AU - Whyte, Carly E

AU - Singh, Kailash

AU - Burton, Oliver T

AU - Aloulou, Meryem

AU - Kouser, Lubna

AU - Veiga, Rafael Valente

AU - Dashwood, Amy

AU - Okkenhaug, Hanneke

AU - Benadda, Samira

AU - Moudra, Alena

AU - Bricard, Orian

AU - Lienart, Stephanie

AU - Bielefeld, Pascal

AU - Roca, Carlos P

AU - Naranjo-Galindo, Francisco José

AU - Lombard-Vadnais, Félix

AU - Junius, Steffie

AU - Bending, David

AU - Hochepied, Tino

AU - Halim, Timotheus Y F

AU - Schlenner, Susan

AU - Lesage, Sylvie

AU - Dooley, James

AU - Liston, Adrian

PY - 2022/7/4

Y1 - 2022/7/4

N2 - Interleukin 2 (IL-2) is a key homeostatic cytokine, with therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical use has been hampered by pleiotropic functionality and widespread receptor expression, with unexpected adverse events. Here, we developed a novel mouse strain to divert IL-2 production, allowing identification of contextual outcomes. Network analysis identified priority access for Tregs and a competitive fitness cost of IL-2 production among both Tregs and conventional CD4 T cells. CD8 T and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified Tregs, whereas IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8+ Tregs and ILC2 cells, the latter driving a downstream, IL-5-mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain adverse effects observed during clinical trials. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability.

AB - Interleukin 2 (IL-2) is a key homeostatic cytokine, with therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical use has been hampered by pleiotropic functionality and widespread receptor expression, with unexpected adverse events. Here, we developed a novel mouse strain to divert IL-2 production, allowing identification of contextual outcomes. Network analysis identified priority access for Tregs and a competitive fitness cost of IL-2 production among both Tregs and conventional CD4 T cells. CD8 T and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified Tregs, whereas IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8+ Tregs and ILC2 cells, the latter driving a downstream, IL-5-mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain adverse effects observed during clinical trials. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability.

KW - Animals

KW - Immunity, Innate

KW - Interleukin-2/biosynthesis

KW - Killer Cells, Natural/immunology

KW - Mice

KW - T-Lymphocytes, Regulatory/immunology

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U2 - 10.1084/jem.20212391

DO - 10.1084/jem.20212391

M3 - Article

C2 - 35699942

SN - 0022-1007

VL - 219

JO - The Journal of Experimental Medicine

JF - The Journal of Experimental Medicine

IS - 7

M1 - e20212391

ER -

Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits

Abstract

Bibliographical note

Keywords

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Projects

Negative feedback control of T cells in tolerance and cancer - from pathways to biomarkers

Cite this