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

Yshii, Lidia; Pasciuto, Emanuela; Bielefeld, Pascal; Mascali, Loriana; Lemaitre, Pierre; Marino, Marika; Dooley, James; Kouser, Lubna; Verschoren, Stijn; Lagou, Vasiliki; Kemps, Hannelore; Gervois, Pascal; de Boer, Antina; Burton, Oliver T; Wahis, Jerome; Verhaert, Jens; Tareen, Samar; Roca, Carlos P; Singh, Kailash; Whyte, Carly E; Kerstens, Axelle; Callaerts-Vegh, Zsuzsanna; Poovathingal, Suresh; Prezzemolo, Teresa; Wierda, Keimpe; Dashwood, Amy; Xie, Junhua; Van Wonterghem, Elien; Creemers, Eline; Aloulou, Meryem; Gsell, Willy; Abiega, Oihane; Munck, Sebastian; Vandenbroucke, Roosmarijn E; Bronckaers, Annelies; Lemmens, Robin; De Strooper, Bart; Van Den Bosch, Ludo; Himmelreich, Uwe; Fitzsimons, Carlos P; Holt, Matthew G; Liston, Adrian

doi:10.1038/s41590-022-01208-z

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

Author:

Yshii, Lidia

Pasciuto, Emanuela ; Bielefeld, Pascal ; Mascali, Loriana ; Lemaitre, Pierre ; Marino, Marika ; Dooley, James ; Kouser, Lubna ; Verschoren, Stijn ; Lagou, Vasiliki ; Kemps, Hannelore ; Gervois, Pascal ; de Boer, Antina ; Burton, Oliver T ; Wahis, Jerome ; Verhaert, Jens ; Tareen, Samar ; Roca, Carlos P ; Singh, Kailash ; Whyte, Carly E ; Kerstens, Axelle ; Callaerts-Vegh, Zsuzsanna ; Poovathingal, Suresh ; Prezzemolo, Teresa ; Wierda, Keimpe ; Dashwood, Amy ; Xie, Junhua ; Van Wonterghem, Elien ; Creemers, Eline ; Aloulou, Meryem ; Gsell, Willy ; Abiega, Oihane ; Munck, Sebastian ; Vandenbroucke, Roosmarijn E ; Bronckaers, Annelies ; Lemmens, Robin ; De Strooper, Bart ; Van Den Bosch, Ludo ; Himmelreich, Uwe ; Fitzsimons, Carlos P ; Holt, Matthew G ; Liston, Adrian

Keywords:

Science & Technology, Life Sciences & Biomedicine, Immunology, REG-CELLS, EXPRESSION, MICROGLIA, THERAPY, PACKAGE, SYSTEM, REPAIR, Animals, Astrocytes, Biological Products, Brain, Humans, Interleukin-2, Interleukins, Mice, Neuroinflammatory Diseases, T-Lymphocytes, Regulatory, 12V7519N#54771050, 12V7522N#56382420, 1107 Immunology, 3101 Biochemistry and cell biology, 3204 Immunology

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.