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, Masahiro Ono, Tino Hochepied, Timotheus Y.F. Halim, Susan Schlenner, Sylvie Lesage, James Dooley, Adrian Liston, Université de Montréal. Faculté de médecine. Département de microbiologie, infectiologie et immunologie, Whyte, Carly E [0000-0001-6556-6855], Singh, Kailash [0000-0002-6771-7757], Burton, Oliver T [0000-0003-3884-7373], Aloulou, Meryem [0000-0003-4590-230X], Kouser, Lubna [0000-0002-3592-7768], Veiga, Rafael Valente [0000-0002-4413-193X], Dashwood, Amy [0000-0002-4340-377X], Okkenhaug, Hanneke [0000-0003-0669-4069], Benadda, Samira [0000-0002-3067-8125], Moudra, Alena [0000-0003-3465-7812], Bricard, Orian [0000-0003-3976-7228], Lienart, Stephanie [0000-0002-5825-6979], Bielefeld, Pascal [0000-0001-9308-2321], Roca, Carlos P [0000-0003-0230-1926], Naranjo-Galindo, Francisco José [0000-0001-8225-3906], Lombard-Vadnais, Félix [0000-0002-0045-4382], Junius, Steffie [0000-0003-0491-6887], Bending, David [0000-0003-0071-1163], Ono, Masahiro [0000-0002-9284-7326], Hochepied, Tino [0000-0001-5897-2054], Halim, Timotheus YF [0000-0001-9773-0023], Schlenner, Susan [0000-0002-8553-3388], Lesage, Sylvie [0000-0002-0968-2795], Dooley, James [0000-0003-3154-4708], Liston, Adrian [0000-0002-6272-4085], and Apollo - University of Cambridge Repository
Funder: Fondation pour l'Aide à la Recherche sur la Sclérose en Plaques, Funder: Alzheimer's Association, Funder: European Research Council, Funder: Fondation pour l’Aide à la Recherche sur la Sclérose en Plaques, Funder: Vetenskapsrådet, Funder: Alzheimer’s Association, Funder: Fonds Wetenschappelijk Onderzoek, Funder: Vlaams Instituut voor Biotechnologie, 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.