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

• Published in: The Journal of clinical investigation 2016-04, Vol.126 (4), p.1413-1424
• Main Authors: MacDonald, Katherine G, Hoeppli, Romy E, Huang, Qing, Gillies, Jana, Luciani, Dan S, Orban, Paul C, Broady, Raewyn, Levings, Megan K
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI82771

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.