Antigen receptor-engineered Tregs inhibit CNS autoimmunity in cell therapy using nonredundant immune mechanisms in mice.

Autor: Pohar J; Institut Necker Enfants Malades, Institut National de la Santé et de la Recherche Médicale INSERM U1151 - Centre National de la Recherche Scientifique CNRS UMR 8253, Paris, France., O'Connor R; University of Edinburgh, Edinburgh, UK., Manfroi B; Institut Necker Enfants Malades, Institut National de la Santé et de la Recherche Médicale INSERM U1151 - Centre National de la Recherche Scientifique CNRS UMR 8253, Paris, France., El-Behi M; Institut Necker Enfants Malades, Institut National de la Santé et de la Recherche Médicale INSERM U1151 - Centre National de la Recherche Scientifique CNRS UMR 8253, Paris, France., Jouneau L; Université Paris-Saclay, INRAE, UVSQ, VIM, Jouy-en-Josas, France., Boudinot P; Université Paris-Saclay, INRAE, UVSQ, VIM, Jouy-en-Josas, France., Bunse M; Max Delbrück Center for Molecular Medicine, The Helmholtz Association, Berlin, Germany., Uckert W; Max Delbrück Center for Molecular Medicine, The Helmholtz Association, Berlin, Germany., Luka M; Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, Université de Paris, Imagine Institute, Paris, France.; Labtech Single-Cell@Imagine, Imagine Institute, Paris, France., Ménager M; Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, Université de Paris, Imagine Institute, Paris, France.; Labtech Single-Cell@Imagine, Imagine Institute, Paris, France., Liblau R; Infinity-Institut Toulousain des Maladies Infectieuses et Inflammatoires, Université Toulouse III, Toulouse, France., Anderton SM; University of Edinburgh, Edinburgh, UK., Fillatreau S; Institut Necker Enfants Malades, Institut National de la Santé et de la Recherche Médicale INSERM U1151 - Centre National de la Recherche Scientifique CNRS UMR 8253, Paris, France.; Université de Paris, Faculté de Médecine, Paris, France.; AP-HP, Hôpital Necker-Enfants Malades, Paris, France.
Jazyk: angličtina
Zdroj: European journal of immunology [Eur J Immunol] 2022 Aug; Vol. 52 (8), pp. 1335-1349. Date of Electronic Publication: 2022 May 27.
DOI: 10.1002/eji.202249845
Abstrakt: CD4 + FOXP3 + Tregs are currently explored to develop cell therapies against immune-mediated disorders, with an increasing focus on antigen receptor-engineered Tregs. Deciphering their mode of action is necessary to identify the strengths and limits of this approach. Here, we addressed this issue in an autoimmune disease of the CNS, EAE. Following disease induction, autoreactive Tregs upregulated LAG-3 and CTLA-4 in LNs, while IL-10 and amphiregulin (AREG) were increased in CNS Tregs. Using genetic approaches, we demonstrated that IL-10, CTLA-4, and LAG-3 were nonredundantly required for the protective function of antigen receptor-engineered Tregs against EAE in cell therapy whereas AREG was dispensable. Treg-derived IL-10 and CTLA-4 were both required to suppress acute autoreactive CD4 + T-cell activation, which correlated with disease control. These molecules also affected the accumulation in the recipients of engineered Tregs themselves, underlying complex roles for these molecules. Noteworthy, despite the persistence of the transferred Tregs and their protective effect, autoreactive T cells eventually accumulated in the spleen of treated mice. In conclusion, this study highlights the remarkable power of antigen receptor-engineered Tregs to appropriately provide multiple suppressive factors nonredundantly necessary to prevent autoimmune attacks.
(© 2022 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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