Tregs with an MHC class II peptide–specific chimeric antigen receptor prevent autoimmune diabetes in mice

Adoptive immunotherapy with Tregs is a promising approach for preventing or treating type 1 diabetes. Islet antigenspecific Tregs have more potent therapeutic effects than polyclonal cells, but their low frequency is a barrier for clinical application. To generate Tregs that recognize islet antigens...

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Bibliographic Details
Published in:The Journal of clinical investigation 2023-09, Vol.133 (18), p.1-13
Main Authors: Spanier, Justin A, Fung, Vivian, Wardell, Christine M, Alkhatib, Mohannad H, Chen, Yixin, Swanson, Linnea A, Dwyer, Alexander J, Weno, Matthew E, Silva, Nubia, Mitchell, Jason S, Orban, Paul C, Mojibian, Majid, Verchere, C Bruce, Fife, Brian T, Levings, Megan K
Format: Article
Language:English
Subjects:
Adoptive immunotherapy
Adoptive transfer
Antibodies
Antigens
Autoimmune diseases
Biomedical research
CD80 antigen
CD86 antigen
Cell growth
Cell proliferation
Chimeric antigen receptors
Dendritic cells
Diabetes
Diabetes mellitus (insulin dependent)
Immunodeficiency
Immunotherapy
Insulin
Lymphocytes
Lymphocytes T
Major histocompatibility complex
Monoclonal antibodies
Peptides
T cell receptors
Transcription factors
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Summary:Adoptive immunotherapy with Tregs is a promising approach for preventing or treating type 1 diabetes. Islet antigenspecific Tregs have more potent therapeutic effects than polyclonal cells, but their low frequency is a barrier for clinical application. To generate Tregs that recognize islet antigens, we engineered a chimeric antigen receptor (CAR) derived from a monoclonal antibody with specificity forthe insulin В chain 10-23 peptide presented in the context of the IA;7 MHC class II allele present in NOD mice. Peptide specificity of the resulting InsB-g? CAR was confirmed by tetramer staining and T cell proliferation in response to recombinant or islet-derived peptide. The lnsB-g7 CAR redirected NOD Treg specificity such that insulin В 10-23-peptide stimulation enhanced suppressive function, measured via reduction of proliferation and IL-2 production by BDC2.5 T cells and CD80 and CD86 expression on dendritic cells. Cotransfer of lnsB-g7 CAR Tregs prevented adoptive transfer diabetes by BDC2.5 T cells in immunodeficient NOD mice. In WT NOD mice, lnsB-g7 CAR Tregs prevented spontaneous diabetes. These results show that engineering Treg specificity for islet antigens using a T cell receptor-like CAR is a promisingtherapeutic approach forthe prevention of autoimmune diabetes.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI168601.