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

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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 | Wahis, Jérôme | Verhaert, Jens | Tareen, Samar | Roca, Carlos | Singh, Kailash | Whyte, Carly | 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 | Bronckaers, Annelies | Lemmens, Robin | de Strooper, Bart | van den Bosch, Ludo | Himmelreich, Uwe | Fitzsimons, Carlos | Holt, Matthew | Liston, Adrian

Edité par CCSD ; Nature Publishing Group -

International audience. 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 (T reg ) 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 T reg 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.

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