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1. Regulatory T cells limit age-associated retinal inflammation and neurodegeneration

Author

María Llorián-Salvador, Alerie G. de la Fuente, Christopher E. McMurran, Amy Dashwood, James Dooley, Adrian Liston, Rosana Penalva, Yvonne Dombrowski, Alan W. Stitt, and Denise C. Fitzgerald

Subjects
Ageing, Inflammation, Neurodegeneration, Regulatory T cells, Retina, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Abstract Background Ageing is the principal risk factor for retinal degenerative diseases, which are the commonest cause of blindness in the developed countries. These conditions include age-related macular degeneration or diabetic retinopathy. Regulatory T cells play a vital role in immunoregulation of the nervous system by limiting inflammation and tissue damage in health and disease. Because the retina was long-considered an immunoprivileged site, the precise contribution of regulatory T cells in retinal homeostasis and in age-related retinal diseases remains unknown. Methods Regulatory T cells were selectively depleted in both young (2–4 months) and aged (18–23 months) FoxP3-DTR mice. We evaluated neuroretinal degeneration, gliosis, subretinal space phagocyte infiltration, and retinal pigmented epithelium morphology through immunofluorescence analysis. Subsequently, aged Treg depleted animals underwent adoptive transfer of both young and aged regulatory T cells from wild-type mice, and the resulting impact on neurodegeneration was assessed. Statistical analyses employed included the U-Mann Whitney test, and for comparisons involving more than two groups, 1-way ANOVA analysis followed by Bonferroni’s post hoc test. Results Our study shows that regulatory T cell elimination leads to retinal pigment epithelium cell dysmorphology and accumulation of phagocytes in the subretinal space of young and aged mice. However, only aged mice experience retinal neurodegeneration and gliosis. Surprisingly, adoptive transfer of young but not aged regulatory T cells reverse these changes. Conclusion Our findings demonstrate an essential role for regulatory T cells in maintaining age retinal homeostasis and preventing age-related neurodegeneration. This previously undescribed role of regulatory T cells in limiting retinal inflammation, RPE/choroid epithelium damage and subsequently photoreceptor loss with age, opens novel avenues to explore regulatory T cell neuroprotective and anti-inflammatory properties as potential therapeutic approaches for age-related retinal diseases.

Published
2024
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2. Ageing impairs the regenerative capacity of regulatory T cells in mouse central nervous system remyelination

Author

Alerie Guzman de la Fuente, Marie Dittmer, Elise J. Heesbeen, Nira de la Vega Gallardo, Jessica A. White, Andrew Young, Tiree McColgan, Amy Dashwood, Katie Mayne, Sonia Cabeza-Fernández, John Falconer, Francisco Javier Rodriguez-Baena, Christopher E. McMurran, Mohammed Inayatullah, Khalil S. Rawji, Robin J. M. Franklin, James Dooley, Adrian Liston, Rebecca J. Ingram, Vijay K. Tiwari, Rosana Penalva, Yvonne Dombrowski, and Denise C. Fitzgerald

Subjects
Science
Abstract

Abstract Myelin regeneration (remyelination) is essential to prevent neurodegeneration in demyelinating diseases such as Multiple Sclerosis, however, its efficiency declines with age. Regulatory T cells (Treg) recently emerged as critical players in tissue regeneration, including remyelination. However, the effect of ageing on Treg-mediated regenerative processes is poorly understood. Here, we show that expansion of aged Treg does not rescue age-associated remyelination impairment due to an intrinsically diminished capacity of aged Treg to promote oligodendrocyte differentiation and myelination in male and female mice. This decline in regenerative Treg functions can be rescued by a young environment. We identified Melanoma Cell Adhesion Molecule 1 (MCAM1) and Integrin alpha 2 (ITGA2) as candidates of Treg-mediated oligodendrocyte differentiation that decrease with age. Our findings demonstrate that ageing limits the neuroregenerative capacity of Treg, likely limiting their remyelinating therapeutic potential in aged patients, and describe two mechanisms implicated in Treg-driven remyelination that may be targetable to overcome this limitation.

Published
2024
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3. Correction: 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, and Adrian Liston

Subjects
Immunology, Immunology and Allergy
Published
2022

4. 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

5. 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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