Successful Regulatory T Cell-Based Therapy Relies on Inhibition of T Cell Effector Function and Enrichment of FOXP3+Cells in a Humanized Mouse Model of Skin Inflammation

Autor: V.L. de Oliveira, Irma Joosten, Stijn C. G. Bauland, P.E.J. van Erp, M. Peppelman, Esther Fasse, Sija Landman, Hans J. P. M. Koenen, E. van Rijssen
Rok vydání: 2020
Předmět:
Article Subject
Regulatory T cell
T cell
medicine.medical_treatment
Transplantation
Heterologous
Immunology
chemical and pharmacologic phenomena
Inflammation
Mice
SCID
Immunotherapy
Adoptive
T-Lymphocytes
Regulatory
Proinflammatory cytokine
Mice
03 medical and health sciences
All institutes and research themes of the Radboud University Medical Center
0302 clinical medicine
Immune system
T-Lymphocyte Subsets
Immune Tolerance
Animals
Humans
Immunology and Allergy
Medicine
Cells
Cultured
Cell Proliferation
Skin
030304 developmental biology
0303 health sciences
integumentary system
business.industry
FOXP3
Forkhead Transcription Factors
hemic and immune systems
Skin Transplantation
General Medicine
Immunotherapy
RC581-607
Disease Models
Animal
medicine.anatomical_structure
030220 oncology & carcinogenesis
Humanized mouse
Female
Immunologic diseases. Allergy
medicine.symptom
business
Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5]
Research Article
Zdroj: Journal of Immunology Research, 14
Journal of Immunology Research, Vol 2020 (2020)
Journal of Immunology Research
ISSN: 2314-8861
Popis: Background. Recent clinical trials using regulatory T cells (Treg) support the therapeutic potential of Treg-based therapy in transplantation and autoinflammatory diseases. Despite these clinical successes, the effect of Treg on inflamed tissues, as well as their impact on immune effector function in vivo, is poorly understood. Therefore, we here evaluated the effect of human Treg injection on cutaneous inflammatory processes in vivo using a humanized mouse model of human skin inflammation (huPBL-SCID-huSkin). Methods. SCID beige mice were transplanted with human skin followed by intraperitoneal (IP) injection of 20‐40×106 allogeneic human PBMCs. This typically results in human skin inflammation as indicated by epidermal thickening (hyperkeratosis) and changes in dermal inflammatory markers such as the antimicrobial peptide hBD2 and epidermal barrier cytokeratins K10 and K16, as well as T cell infiltration in the dermis. Ex vivo-expanded human Treg were infused intraperitoneally. Human cutaneous inflammation and systemic immune responses were analysed by immunohistochemistry and flow cytometry. Results. We confirmed that human Treg injection inhibits skin inflammation and the influx of effector T cells. As a novel finding, we demonstrate that human Treg injection led to a reduction of IL-17-secreting cells while promoting a relative increase in immunosuppressive FOXP3+ Treg in the human skin, indicating active immune regulation in controlling the local proinflammatory response. Consistent with the local control (skin), systemically (splenocytes), we observed that Treg injection led to lower frequencies of IFNγ and IL-17A-expressing human T cells, while a trend towards enrichment of FOXP3+ Treg was observed. Conclusion. Taken together, we demonstrate that inhibition of skin inflammation by Treg infusion, next to a reduction of infiltrating effector T cells, is mediated by restoring both the local and systemic balance between cytokine-producing effector T cells and immunoregulatory T cells. This work furthers our understanding of Treg-based immunotherapy.
Databáze: OpenAIRE
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