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

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 st...

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Bibliographic Details
Published in:The Journal of experimental medicine 2022-07, Vol.219 (7)
Main Authors: Whyte, Carly E, Singh, Kailash, Burton, Oliver T, Aloulou, Meryem, Kouser, Lubna, Veiga, Rafael Valente, Dashwood, Amy, Okkenhaug, Hanneke, Benadda, Samira, Moudra, Alena, Bricard, Orian, Lienart, Stephanie, Bielefeld, Pascal, Roca, Carlos P, Naranjo-Galindo, Francisco José, Lombard-Vadnais, Félix, Junius, Steffie, Bending, David, Ono, Masahiro, Hochepied, Tino, Halim, Timotheus Y F, Schlenner, Susan, Lesage, Sylvie, Dooley, James, Liston, Adrian
Format: Article
Language:English
Subjects:
Animals
Human health and pathology
Immunity, Innate
Interleukin-2 - biosynthesis
Interleukin-2 - immunology
Killer Cells, Natural - immunology
Killer Cells, Natural - metabolism
Life Sciences
Mice
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - metabolism
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Summary: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.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20212391