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

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.