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Article Dans Une Revue Journal of Experimental Medicine Année : 2022

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

Carly E Whyte
Kailash Singh
Lubna Kouser
Amy Dashwood
Alena Moudra
Orian Bricard
Pascal Bielefeld
Carlos P Roca
David Bending
Masahiro Ono
Timotheus Y.F. Halim
Susan Schlenner
Sylvie Lesage
James Dooley
Adrian Liston

Résumé

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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Dates et versions

hal-04067536 , version 1 (13-04-2023)

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Carly E Whyte, Kailash Singh, Oliver T Burton, Meryem Aloulou, Lubna Kouser, et al.. Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits. Journal of Experimental Medicine, 2022, 219 (7), pp.e20212391. ⟨10.1084/jem.20212391⟩. ⟨hal-04067536⟩
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