title: Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor.
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.forename: Katherine G
authors.initials: KG
authors.lastname: MacDonald
authors.forename: Romy E
authors.initials: RE
authors.lastname: Hoeppli
authors.forename: Qing
authors.initials: Q
authors.lastname: Huang
authors.forename: Jana
authors.initials: J
authors.lastname: Gillies
authors.forename: Dan S
authors.initials: DS
authors.lastname: Luciani
authors.forename: Paul C
authors.initials: PC
authors.lastname: Orban
authors.forename: Raewyn
authors.initials: R
authors.lastname: Broady
authors.forename: Megan K
authors.initials: MK
authors.lastname: Levings
mesh_terms: D000818:Animals; D005260:Female; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007519:Isoantigens / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D015789:HLA-A2 Antigen; D007519:Isoantigens; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins