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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 7

Skin xenograft model of CAR-Treg–mediated suppression.

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Skin xenograft model of CAR-Treg–mediated suppression.
(A) Images of ski...
(A) Images of skin grafts over time. Images shown are representative of 3 experiments with the same donor skin (A) and donor T cells (from donor 1) across mouse groups (repeated with n = 3 donor grafts and n = 3 donor T cells, 1 mouse per group). (B) H&E histology (original magnification, ×4 and ×10) of sections from grafts 2 weeks after Tregs were injected and IHC staining of human CD8 (original magnification, ×10), mCherry (original magnification, ×10), and human Foxp3 (original magnification, ×10), representative images (donor 1/A). Scale bar: 100 μm. (C) CD8+ cells quantified from CD8 IHC-stained graft sections in areas just below the dermal/epidermal junction. The number of cells was counted per high power field (hpf; original magnification, ×400). ****P < 0.0001, by 1-way ANOVA with respect to control (Teff EGFR alone) with Dunnett test for multiple comparisons. Tr, Treg.

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