Journal Article

Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor

Huang, Qing, MacDonald, Katherine G., Luciani, Dan S., Orban, Paul C., Hoeppli, Romy E., Levings, Megan K., Gillies, Jana, Broady, Raewyn

2016

Overview

Adoptive immunotherapy with regulatory T cells (Tregs) is a promising treatment for allograft rejection and graft-versus-host disease (GVHD). Emerging data indicate that, compared with polyclonal Tregs, disease-relevant antigen-specific Tregs may have numerous advantages, such as a need for fewer cells and reduced risk of nonspecific immune suppression. Current methods to generate alloantigen-specific Tregs rely on expansion with allogeneic antigen-presenting cells, which requires access to donor and recipient cells and multiple MHC mismatches. The successful use of chimeric antigen receptors (CARs) for the generation of antigen-specific effector T cells suggests that a similar approach could be used to generate alloantigen-specific Tregs. Here, we have described the creation of an HLA-A2-specific CAR (A2-CAR) and its application in the generation of alloantigen-specific human Tregs. In vitro, A2-CAR-expressing Tregs maintained their expected phenotype and suppressive function before, during, and after A2-CAR-mediated stimulation. In mouse models, human A2-CAR-expressing Tregs were superior to Tregs expressing an irrelevant CAR at preventing xenogeneic GVHD caused by HLA-A2+ T cells. Together, our results demonstrate that use of CAR technology to generate potent, functional, and stable alloantigen-specific human Tregs markedly enhances their therapeutic potential in transplantation and sets the stage for using this approach for making antigen-specific Tregs for therapy of multiple diseases.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Antigens / Biomedical research / Cell receptors / Cloning / Colleges & universities / Diabetes / Experiments / Female / Flow cytometry / Genetic aspects / Growth / HLA-A2 Antigen - genetics / HLA-A2 Antigen - immunology / Humans / Immunotherapy / Innovations / Isoantigens - genetics / Isoantigens - immunology / Laboratories / Lymphocytes / Male / Mice / Properties / Receptors, Antigen, T-Cell - genetics / Receptors, Antigen, T-Cell - immunology / Recombinant Fusion Proteins - genetics / Recombinant Fusion Proteins - immunology / T cell receptors / T cells / T-Lymphocytes, Regulatory - immunology / Transplants & implants