GPA33: A Marker to Identify Stable Human Regulatory T Cells
| Autor: | Opstelten, Rianne, de Kivit, Sander, Slot, Manon C, van den Biggelaar, Maartje, Iwaszkiewicz-Grześ, Dorota, Gliwiński, Mateusz, Scott, Andrew M, Blom, Bianca, Trzonkowski, Piotr, Borst, Jannie, Cuadrado, Eloy, Amsen, Derk, Afd Pharmaceutics, Pharmaceutics |
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| Přispěvatelé: | Graduate School, AII - Inflammatory diseases, Experimental Immunology, Landsteiner Laboratory, Afd Pharmaceutics, Pharmaceutics |
| Rok vydání: | 2020 |
| Předmět: |
Immunology
Biology Lymphocyte Activation T-Lymphocytes Regulatory Proinflammatory cytokine Cell therapy Transcriptome 03 medical and health sciences 0302 clinical medicine Transforming Growth Factor beta Immune Tolerance Humans Immunology and Allergy Epigenetics Enhancer Transcription factor Cells Cultured Inflammation Membrane Glycoproteins Cell growth Forkhead Transcription Factors In vitro Cell biology Cytokines Biomarkers 030215 immunology |
| Zdroj: | Journal of Immunology, 204(12), 3139-3148. AMER ASSOC IMMUNOLOGISTS Journal of Immunology, 204(12), 3139. American Association of Immunologists Journal of immunology (Baltimore, Md., 204(12), 3139-3148. American Association of Immunologists |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1901250 |
| Popis: | FOXP3-expressing regulatory T (Treg) cells safeguard immunological tolerance. Treg cells can be generated during thymic development (called thymic Treg [tTreg] cells) or derived from mature conventional CD4+ T cells that underwent TGF-β–mediated conversion in the periphery (called peripheral Treg [pTreg] cells). Murine studies have shown that tTreg cells exhibit strong lineage fidelity, whereas pTreg cells can revert into conventional CD4+ T cells. Their stronger lineage commitment makes tTreg cells the safest cells to use in adoptive cell therapy, increasingly used to treat autoimmune and inflammatory disorders. Markers to distinguish human tTreg cells from pTreg cells have, however, not been found. Based on combined proteomic and transcriptomic approaches, we report that the Ig superfamily protein GPA33 is expressed on a subset of human Treg cells. GPA33 is acquired late during tTreg cell development but is not expressed on TGF-β–induced Treg cells. GPA33 identifies Treg cells in human blood that lack the ability to produce effector cytokines (IL-2, IFN-γ, IL-17), regardless of differentiation stage. GPA33high Treg cells universally express the transcription factor Helios that preferentially marks tTreg cells and can robustly and stably be expanded in vitro even without rapamycin. Expanded GPA33high Treg cells are suppressive, unable to produce proinflammatory cytokines, and exhibit the epigenetic modifications of the FOXP3 gene enhancer CNS2, necessary for indelible expression of this critical transcription factor. Our findings thus suggest that GPA33 identifies human tTreg cells and provide a strategy to isolate such cells for safer and more efficacious adoptive cell therapy. |
| Databáze: | OpenAIRE |
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