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

TLDR

Regulatory T cells maintain self‑tolerance, and although antigen‑specific Treg transfer is a promising strategy for autoimmune disease and transplant rejection, practical limitations and the lack of established CAR‑Treg approaches have hindered its clinical use, despite CAR T cells’ success against B‑cell lymphomas. The study aimed to generate CD19‑targeted CAR Tregs from human PBMCs and optimize the Treg source fraction (CD4⁺CD25⁺CD127^loCD45RA⁺CD45RO⁻). The engineered CD19‑CAR Tregs were expanded in vitro while retaining Treg markers, including latent TGF‑β, and they inhibited IgG antibody production and B‑cell differentiation through a TGF‑β‑dependent mechanism. In immunodeficient mice reconstituted with human PBMCs, CD19‑CAR Tregs suppressed antibody production without inducing graft‑versus‑host disease, suggesting that adoptive transfer of these cells could treat autoantibody‑mediated autoimmune diseases.

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.