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

• Published in: American journal of transplantation Vol. 19; no. 1; pp. 62 - 76
• Main Authors: Hoeppli, R. E., MacDonald, K. N., Leclair, P., Fung, V. C. W., Mojibian, M., Gillies, J., Rahavi, S. M. R., Campbell, A. I. M., Gandhi, S. K., Pesenacker, A. M., Reid, G., Lim, C. J., Levings, M. K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 01.01.2019
• Subjects: Animals; basic (laboratory) research/science; CCR9 protein; CD4 antigen; Cell Adhesion; Cell Movement; Cell Proliferation; cellular biology; cellular transplantation (non‐islet); Chemokine CXCL10 - metabolism; chemokines/chemokine receptors; CXCL10 protein; CXCR3 protein; Digestive system; Epigenesis, Genetic; Female; Foxp3 protein; Gastrointestinal tract; Graft rejection; Graft-versus-host reaction; Homing behavior; Homing receptors; Humans; immune regulation; Immune Tolerance; Immunoregulation; Immunosuppression; Immunosuppression Therapy; immunosuppression/immune modulation; Inflammation; Inflammation - immunology; Injection; Integrins - metabolism; Interferon; Interleukin-12 - immunology; intestinal (allograft) function/dysfunction; Intestine; Intestines - immunology; Latency; lymphocyte biology: trafficking; Lymphocytes T; Male; Mice; Pediatrics; Phenotype; Receptors, CCR - metabolism; Receptors, CXCR3 - metabolism; Retinoic acid; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; Th1 Cells - cytology; Therapeutic applications; Thymus; Thymus Gland - immunology; tolerance; translational research/science; lymphocyte biology: trafficking; translational research/science; immunosuppression/immune modulation; cellular biology; chemokines/chemokine receptors; cellular transplantation (non-islet); immune regulation; intestinal (allograft) function/dysfunction; tolerance; basic (laboratory) research/science
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/ajt.14936

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. The migratory ability of human regulatory T cells can be tailored with cytokines or metabolites so they home to specific sites.