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

Author

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

Subjects
INTERFERON, EOSINOPHILIA, RECEPTOR, Immunology, Biology and Life Sciences, EXPANSION, LOW-DOSE INTERLEUKIN-2, T-Lymphocytes, Regulatory, Immunity, Innate, RECOMBINANT INTERLEUKIN-2, ALPHA, Killer Cells, Natural, Mice, DIFFERENTIATION, Medicine and Health Sciences, Immunology and Allergy, GROWTH, Animals, Interleukin-2, REGULATORY T-CELLS
Abstract

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.

Published
2022

2. Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation

Author

Lidia Yshii, Emanuela Pasciuto, Pascal Bielefeld, Loriana Mascali, Pierre Lemaitre, Marika Marino, James Dooley, Lubna Kouser, Stijn Verschoren, Vasiliki Lagou, Hannelore Kemps, Pascal Gervois, Antina de Boer, Oliver T. Burton, Jérôme Wahis, Jens Verhaert, Samar H. K. Tareen, Carlos P. Roca, Kailash Singh, Carly E. Whyte, Axelle Kerstens, Zsuzsanna Callaerts-Vegh, Suresh Poovathingal, Teresa Prezzemolo, Keimpe Wierda, Amy Dashwood, Junhua Xie, Elien Van Wonterghem, Eline Creemers, Meryem Aloulou, Willy Gsell, Oihane Abiega, Sebastian Munck, Roosmarijn E. Vandenbroucke, Annelies Bronckaers, Robin Lemmens, Bart De Strooper, Ludo Van Den Bosch, Uwe Himmelreich, Carlos P. Fitzsimons, Matthew G. Holt, Adrian Liston, Pasciuto, Emanuela [0000-0002-5391-9585], Marino, Marika [0000-0001-6773-6176], Dooley, James [0000-0003-3154-4708], Verschoren, Stijn [0000-0001-6733-3481], Kemps, Hannelore [0000-0001-9248-1697], Gervois, Pascal [0000-0002-8320-1320], Burton, Oliver T [0000-0003-3884-7373], Singh, Kailash [0000-0002-6771-7757], Whyte, Carly E [0000-0001-6556-6855], Callaerts-Vegh, Zsuzsanna [0000-0001-9091-2078], Dashwood, Amy [0000-0002-4340-377X], Gsell, Willy [0000-0001-7334-6107], Vandenbroucke, Roosmarijn E [0000-0002-8327-620X], Liston, Adrian [0000-0002-6272-4085], Apollo - University of Cambridge Repository, Benson-Rumiz, Alicia, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Amsterdam [Amsterdam] (UvA), The Babraham Institute [Cambridge, UK], Brunel University London [Uxbridge], Hasselt University (UHasselt), Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), VIB [Belgium], VIB-UGent Center for Inflammation Research [Gand, Belgique] (IRC), Universiteit Gent = Ghent University (UGENT), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University Hospitals Leuven [Leuven], University College of London [London] (UCL), Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto = University of Porto, Pasciuto, Emanuela/0000-0002-5391-9585, Aloulou, Meryem/0000-0003-4590-230X, Dooley, James/0000-0003-3154-4708, Verschoren, Stijn/0000-0001-6733-3481, Kemps, Hannelore/0000-0001-9248-1697, Marino, Marika/0000-0001-6773-6176, Lemaitre, Pierre/0000-0003-0687-8685, Structural and Functional Plasticity of the nervous system (SILS, FNWI), SILS Other Research (FNWI), and Instituto de Investigação e Inovação em Saúde

Subjects
EXPRESSION, Immunology, Neuroimmunology, 631/250/127/1213, THERAPY, T-Lymphocytes, Regulatory, MICROGLIA, Mice, Medicine and Health Sciences, Immunology and Allergy, Animals, Humans, Interleukin-2 / genetics, REPAIR, Biological Products, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Interleukins, article, Biology and Life Sciences, 631/250/371, Brain, 631/250/251, REG-CELLS, Regulatory T cells, Astrocytes, 631/250/1619/554/1898/1271, Neuroinflammatory Diseases, Interleukin-2, Immunotherapy, SYSTEM, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, PACKAGE
Abstract

The ability of immune-modulating biologics to prevent and reverse pathology has transformed recent clinical practice. Full utility in the neuroinflammation space, however, requires identification of both effective targets for local immune modulation and a delivery system capable of crossing the blood-brain barrier. The recent identification and characterization of a small population of regulatory T (Treg) cells resident in the brain presents one such potential therapeutic target. Here, we identified brain interleukin 2 (IL-2) levels as a limiting factor for brain-resident Treg cells. We developed a gene-delivery approach for astrocytes, with a small-molecule on-switch to allow temporal control, and enhanced production in reactive astrocytes to spatially direct delivery to inflammatory sites. Mice with brain-specific IL-2 delivery were protected in traumatic brain injury, stroke and multiple sclerosis models, without impacting the peripheral immune system. These results validate brain-specific IL-2 gene delivery as effective protection against neuroinflammation, and provide a versatile platform for delivery of diverse biologics to neuroinflammatory patients. The work was supported by the VIB, an ERC Consolidator Grant TissueTreg (to A.L.), an ERC Proof of Concept Grant TreatBrainDamage (to A.L.), an ERC Starting Grant AstroFunc (to M.G.H.), an ERC Proof of Concept Grant AD-VIP (to M.G.H.), FWO Research Grant 1513616N (to M.G.H.), Thierry Latran Foundation Grant SOD-VIP (to M.G.H.), an ERNAET Chair (H2020-WIDESPREAD-2018-2020-6; NCBio: 951923; to M.G.H.), FWO Research Grants 1503420N (to E.P.) and 1513020N (to J.W.), an SAO-FRA pilot grant (20190032, to E.P.), and the Biotechnology and Biological Sciences Research Council through Institute Strategic Program Grant funding BBS/E/B/000C0427 and BBS/E/B/000C0428, and the Biotechnology and Biological Sciences Research Council Core Capability Grant to the Babraham Institute. E.P., V.L., M.M., P.G., J.W. and A.d.B. were supported by fellowships from the FWO. R.L. is a senior clinical investigator of FWO Flanders. P.B., O.A. and C.P.F. were supported by an ERA-NET-NEURON grant EJTC 2016 to C.P.F. and by the Netherlands Organization for Scientific research (NWO). The authors acknowledge the important contributions of J. Haughton (VIB) for mouse husbandry, M. Rincon (VIB) for advice on AAV design and production, K. Vennekens for technical support, P. -A. Penttila and the KUL FACS Core, J. Wouters and the KUL Molecular Small Animal Imaging Center (MoSAIC), S. Walker and the Babraham Institute Imaging Core, the VIB Bio-Imaging Core, the VIB Single Cell Sequencing Core, and R. Breedijk, M. Hink and the Leeuwenhoek Center for Advanced Microscopy at the University of Amsterdam.

Published
2022

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