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

Hoeppli, RE; MacDonald, KN; Leclair, P; Fung, VCW; Mojibian, M; Gillies, J; Rahavi, SMR; ... Levings, MK; + view all (2019) Tailoring the homing capacity of human Tregs for directed migration to sites of Th1-inflammation or intestinal regions. American Journal of Transplantation , 19 (1) pp. 62-76. 10.1111/ajt.14936. Green open access

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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.

Type: Article
Title: Tailoring the homing capacity of human Tregs for directed migration to sites of Th1-inflammation or intestinal regions
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/ajt.14936
Publisher version: http://doi.org/10.1111/ajt.14936
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
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
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/10063684
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