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Chimeric antigen receptor costimulation domains modulate human regulatory T cell function
Angela C. Boroughs, … , Shadmehr Demehri, Marcela V. Maus
Angela C. Boroughs, … , Shadmehr Demehri, Marcela V. Maus
Published March 14, 2019
Citation Information: JCI Insight. 2019;4(8):e126194. https://doi.org/10.1172/jci.insight.126194.
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Research Article Immunology

Chimeric antigen receptor costimulation domains modulate human regulatory T cell function

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Abstract

Tregs are key modulators of inflammation and are important for the maintenance of peripheral tolerance. Adoptive immunotherapy with polyclonal Tregs holds promise in organ transplantation, graft-versus-host disease, and autoimmune diseases but may be enhanced by antigen-specific, long-lived Tregs. We modified primary human Tregs with chimeric antigen receptors (CARs) bearing different costimulatory domains and performed in vitro analyses of their phenotype and function. While neither the presence of a CAR nor the type of costimulation domain influenced Foxp3 expression in Tregs, the costimulation domain of the CARs affected CAR-Treg surface phenotype and functions, such as cytokine production. Furthermore, signaling from the CD28 costimulation domain maintained CAR-Treg suppressor function, whereas 4-1B costimulation did not. In vivo, CAR-Tregs accumulated at sites expressing target antigen and suppressed antigen-specific effector T cell responses; however, only CAR-Tregs with CD28 signaling domains were potent inhibitors of effector T cell–mediated graft rejection in vivo. Our findings support the use of CD28-based CAR-Tregs for tissue-specific immune suppression in the clinic.

Authors

Angela C. Boroughs, Rebecca C. Larson, Bryan D. Choi, Amanda A. Bouffard, Lauren S. Riley, Erik Schiferle, Anupriya S. Kulkarni, Curtis L. Cetrulo, David Ting, Bruce R. Blazar, Shadmehr Demehri, Marcela V. Maus

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Figure 6

CAR-Tregs accumulate in antigen-expressing tissue in vivo.

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CAR-Tregs accumulate in antigen-expressing tissue in vivo.
(A) U87 s.c. ...
(A) U87 s.c. tumor model for CAR-Treg trafficking experimental outline. U87 WT, WT U87 cells (EGFR+CD19–); U87-CD19, U87 cells transduced with CD19. (B) Representative images of H&E, CD3, and mCherry immunohistochemical staining of U87-CD19 and U87-WT tumors from mice treated with CD19-28ζ CAR-Tregs. Scale bar: 100 μm. (C) Skin xenograft model experimental outline. For each experiment, several mice were grafted with skin from the same human donor (i.e., graft, donor A, B, or C) and then were treated with T cells all derived from a single donor leukopacks (i.e., T cell donor 1, 2, or 3). (D) T cells were quantified from CD3 IHC-stained graft sections in areas just below the dermal/epidermal junction. The number of cells were counted per high-power field (hpf; original magnification, ×400). (E) TUNEL+ cells in the epidermis along the dermal/epidermal junction were quantified/hpf (original magnification, ×2000. n ≤ 2 repeats with different donor skin and donor T cells/experiment). ****adj-P < 0.0001, by 1-way ANOVA with Tukey’s multiple comparisons test (D), and *P < 0.05, by paired t test with donors combined (E).

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