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Am J Transplant. 2019 Jan;19(1):62-76. doi: 10.1111/ajt.14936. Epub 2018 Jun 13.

Tailoring the homing capacity of human Tregs for directed migration to sites of Th1-inflammation or intestinal regions.

Author information

1
Department of Surgery, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada.
2
School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.
3
Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.
4
Department of Pediatrics, University of British Columbia & British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada.

Abstract

Cell-based therapy with CD4+ FOXP3+ regulatory T cells (Tregs) is a promising strategy to limit organ rejection and graft-vs-host disease. Ongoing clinical applications have yet to consider how human Tregs could be modified to direct their migration to specific inflammation sites and/or tissues for more targeted immunosuppression. We show here that stable, homing-receptor-tailored human Tregs can be generated from thymic Tregs isolated from pediatric thymus or adult blood. To direct migration to Th1-inflammatory sites, addition of interferon-γ and IL-12 during Treg expansion produced suppressive, epigenetically stable CXCR3+ TBET+ FOXP3+ T helper (Th)1-Tregs. CXCR3 remained expressed after injection in vivo and Th1-Tregs migrated efficiently towards CXCL10 in vitro. To induce tissue-specific migration, addition of retinoic acid (RA) during Treg expansion induced expression of the gut-homing receptors α4β7-integrin and CCR9. FOXP3+ RA-Tregs had elevated expression of the functional markers latency-associated peptide and glycoprotein A repetitions predominant, increased suppressive capacity in vitro and migrated efficiently to healthy and inflamed intestine after injection into mice. Homing-receptor-tailored Tregs were epigenetically stable even after long-term exposure to inflammatory conditions, suppressive in vivo and characterized by Th1- or gut-homing-specific transcriptomes. Tailoring human thymic Treg homing during in vitro expansion offers a new and clinically applicable approach to improving the potency and specificity of Treg therapy.

KEYWORDS:

basic (laboratory) research/science; cellular biology; cellular transplantation (non-islet); chemokines/chemokine receptors; immune regulation; immunosuppression/immune modulation; intestinal (allograft) function/dysfunction; lymphocyte biology: trafficking; tolerance; translational research/science

PMID:
29766641
DOI:
10.1111/ajt.14936

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