101. Anti-TNF treatment negatively regulates human CD4 + T-cell activation and maturation in vitro, but does not confer an anergic or suppressive phenotype.
- Author
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Povoleri GAM, Lalnunhlimi S, Steel KJA, Agrawal S, O'Byrne AM, Ridley M, Kordasti S, Frederiksen KS, Roberts CA, and Taams LS
- Subjects
- CD4-Positive T-Lymphocytes immunology, Cell Differentiation immunology, Cell Proliferation drug effects, Cells, Cultured, Clonal Anergy drug effects, Clonal Anergy immunology, Humans, Lymphocyte Activation immunology, Phenotype, Tumor Necrosis Factor-alpha antagonists & inhibitors, Adalimumab pharmacology, Anti-Inflammatory Agents pharmacology, CD4-Positive T-Lymphocytes drug effects, Cell Differentiation drug effects, Lymphocyte Activation drug effects
- Abstract
TNF-blockade has shown clear therapeutic value in rheumatoid arthritis and other immune-mediated inflammatory diseases, however its mechanism of action is not fully elucidated. We investigated the effects of TNF-blockade on CD4
+ T cell activation, maturation, and proliferation, and assessed whether TNF-inhibitors confer regulatory potential to CD4+ T cells. CyTOF and flow cytometry analysis revealed that in vitro treatment of human CD4+ T cells with the anti-TNF monoclonal antibody adalimumab promoted IL-10 expression in CD4+ T cells, whilst decreasing cellular activation. In line with this, analysis of gene expression profiling datasets of anti-TNF-treated IL-17 or IFN-γ-producing CD4+ T cells revealed changes in multiple pathways associated with cell cycle and proliferation. Kinetics experiments showed that anti-TNF treatment led to delayed, rather than impaired T-cell activation and maturation. Whilst anti-TNF-treated CD4+ T cells displayed some hyporesponsiveness upon restimulation, they did not acquire enhanced capacity to suppress T-cell responses or modulate monocyte phenotype. These cells however displayed a reduced ability to induce IL-6 and IL-8 production by synovial fibroblasts. Together, these data indicate that anti-TNF treatment delays human CD4+ T-cell activation, maturation, and proliferation, and this reduced activation state may impair their ability to activate stromal cells., (© 2019 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2020
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