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CD19-targeted CAR regulatory T cells suppress B cell pathology without GvHD
Yuki Imura, … , Minako Ito, Akihiko Yoshimura
Yuki Imura, … , Minako Ito, Akihiko Yoshimura
Published June 11, 2020
Citation Information: JCI Insight. 2020;5(14):e136185. https://doi.org/10.1172/jci.insight.136185.
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Research Article Therapeutics

CD19-targeted CAR regulatory T cells suppress B cell pathology without GvHD

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Abstract

Regulatory T cells (Tregs) play essential roles in maintaining immunological self-tolerance and preventing autoimmunity. The adoptive transfer of antigen-specific Tregs has been expected to be a potent therapeutic method for autoimmune diseases, severe allergy, and rejection in organ transplantation. However, effective Treg therapy has not yet been established because of the difficulty in preparing a limited number of antigen-specific Tregs. Chimeric antigen receptor (CAR) T cells have been shown to be a powerful therapeutic method for treating B cell lymphomas, but application of CAR to Treg-mediated therapy has not yet been established. Here, we generated CD19-targeted CAR (CD19-CAR) Tregs from human PBMCs (hPBMCs) and optimized the fraction of the Treg source as CD4+CD25+CD127loCD45RA+CD45RO–. CD19-CAR Tregs could be expanded in vitro while maintaining Treg properties, including high expression of the latent form of TGF-β. CD19-CAR Tregs suppressed IgG antibody production and differentiation of B cells via a TGF-β–dependent mechanism. Unlike conventional CD19-CAR CD8+ T cells, CD19-CAR Tregs suppressed antibody production in immunodeficient mice that were reconstituted with hPBMCs, reducing the risk of graft-versus-host disease. Therefore, the adoptive transfer of CD19-CAR Tregs may provide a novel therapeutic method for treating autoantibody-mediated autoimmune diseases.

Authors

Yuki Imura, Makoto Ando, Taisuke Kondo, Minako Ito, Akihiko Yoshimura

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Figure 3

CD28-based CD19-CAR is better than 4-1BB–based CD19-CAR for CAR Treg generation.

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CD28-based CD19-CAR is better than 4-1BB–based CD19-CAR for CAR Treg gen...
(A) Flow cytometric analysis of Foxp3, Helios, and CTLA-4 in 1928z Tregs and 19BBz Tregs on day 13. (B) Fold expansion on day 13, 8 days after CAR Tregs were sorted (n = 3). (C) Flow cytometric analysis of IL-10 in the indicated cells 4 hours after stimulation with hCD19-K562 cells, K562 cells, or PMA/ionomycin (n = 2). (D) Flow cytometric analysis of LAP and GARP in the indicated cells 1 day after coculture with hCD19-K562 or K562 cells (n = 2) (E) Amount of TGF-β1 produced by CD19-CAR Tregs (1928z) and 19BBz Tregs 1 day after coculture with hCD19-K562 cells or K562 cells (n = 3). Data were collected using human samples provided by 1 healthy donor. P values were determined using (B) 2-tailed Student’s t test or (E) 1-way ANOVA (**P < 0.01). Data are presented as mean ± SEM.

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