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.
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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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