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Anti-TNF treatment negatively regulates human CD4+ T-cell activation and maturation in vitro, but does not confer an anergic or suppressive phenotype

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)445-458
Number of pages14
JournalEuropean Journal of Immunology
Volume50
Issue number3
Early online date13 Nov 2019
DOIs
Publication statusPublished - Mar 2020

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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.

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