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Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor
Katherine G. MacDonald, … , Raewyn Broady, Megan K. Levings
Katherine G. MacDonald, … , Raewyn Broady, Megan K. Levings
Published March 21, 2016
Citation Information: J Clin Invest. 2016;126(4):1413-1424. https://doi.org/10.1172/JCI82771.
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Technical Advance Immunology Transplantation

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

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Abstract

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.

Authors

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

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Figure 1

Construction, expression, and antigen specificity of an HLA-A2–specific CAR.

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Construction, expression, and antigen specificity of an HLA-A2–specific ...
(A) Schematic of domains in the A2-CAR. Gly, glycine serine linker; Myc, Myc-tag; TM, transmembrane. (B) Schematic of bidirectional lentiviral vectors encoding the truncated nerve growth factor receptor (ΔNGFR) as a selectable marker under a minimal CMV promoter and CARs specific for HLA-A2 or HER2 under the EF1α promoter. (C) 293T cells were transfected with an empty vector (ΔNGFR), or a vector encoding a HER2-CAR, or the A2-CAR. Surface expression was measured by detection of the Myc-epitope tag by flow cytometry. UT, untransfected. (D) 293T cells expressing the HER2-CAR or A2-CAR were stained with HLA-A2 or HLA-A24 tetramers (tet). Data are representative of 2 independent experiments.
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