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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.

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


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.


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


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