Induced regulatory T cells are phenotypically unstable and do not protect mice from rapidly progressive glomerulonephritis
| Autor: | A. Richard Kitching, Maliha A. Alikhan, Stephen R. Holdsworth, Joanna R. Ghali |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine medicine.drug_class Receptor expression Immunology Biology Monoclonal antibody T-Lymphocytes Regulatory Mice 03 medical and health sciences Glomerulonephritis 0302 clinical medicine Immune system T-Lymphocyte Subsets In vivo RAR-related orphan receptor gamma medicine Animals Humans Immunology and Allergy Hypersensitivity Delayed Cells Cultured Cell Proliferation Skin Immunosuppression Therapy Mice Knockout FOXP3 Forkhead Transcription Factors Original Articles Nuclear Receptor Subfamily 1 Group F Member 3 medicine.disease In vitro Disease Models Animal 030104 developmental biology Cellular Microenvironment CD4 Antigens 030215 immunology |
| Zdroj: | Immunology. 150:100-114 |
| ISSN: | 0019-2805 |
| Popis: | Regulatory T (Treg) cells are a suppressive CD4+ T‐cell subset. We generated induced Treg (iTreg) cells and explored their therapeutic potential in a murine model of rapidly progressive glomerulonephritis. Polyclonal naive CD4+ T cells were cultured in vitro with interleukin‐2 (IL‐2), transforming growth factor‐β1, all‐trans‐retinoic acid and monoclonal antibodies against interferon‐γ and IL‐4, generating Foxp3+ iTreg cells. To enhance their suppressive phenotype, iTreg cultures were modified with the addition of a monoclonal antibody against IL‐12p40 or by using ROR γt–/– CD4+ T cells. Induced Treg cells were transferred into models of delayed‐type hypersensitivity and experimental glomerulonephritis. The iTreg cells exhibited comparable surface receptor expression and in vitro suppressive ability to natural Treg cells, but did not regulate antigen‐specific delayed‐type hypersensitivity or systemic inflammatory immune responses, losing Foxp3 expression in vivo. In glomerulonephritis, transferred iTreg cells did not prevent renal injury or modulate systemic T helper type 1 immune responses. Induced Treg cells cultured with anti‐IL‐12p40 had an enhanced suppressive phenotype in vitro and regulated dermal delayed‐type hypersensitivity in vivo, but were not protective against renal injury, losing Foxp3 expression, especially in the transferred cells recruited to the kidney. Use of ROR γt–/– CD4+ T cells or iTreg cells generated from sensitized CD4+ Foxp3– cells did not regulate renal or systemic inflammatory responses in vivo. In conclusion, iTreg cells suppress T‐cell proliferation in vitro, but do not regulate experimental glomerulonephritis, being unstable in this inflammatory milieu in vivo. |
| Databáze: | OpenAIRE |
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