%A Roberts,Ceri A. %A Durham,Lucy E. %A Fleskens,Veerle %A Evans,Hayley G. %A Taams,Leonie S. %D 2017 %J Frontiers in Immunology %C %F %G English %K Tumor necrosis factor,Anti-TNF,TNF inhibitors,Adalimumab,Interleukin-10,CD4+ T cell polarization,CD8+ T cell polarization,IL-10 regulation %Q %R 10.3389/fimmu.2017.00157 %W %L %M %P %7 %8 2017-February-15 %9 Original Research %+ Leonie S. Taams,Division of Immunology, Infection and Inflammatory Disease (DIIID), Centre for Inflammation Biology and Cancer Immunology (CIBCI), King’s College London,UK,leonie.taams@kcl.ac.uk %# %! Anti-TNF maintains IL-10+CD4+/CD8+ T cells %* %< %T TNF Blockade Maintains an IL-10+ Phenotype in Human Effector CD4+ and CD8+ T Cells %U https://www.frontiersin.org/articles/10.3389/fimmu.2017.00157 %V 8 %0 JOURNAL ARTICLE %@ 1664-3224 %X CD4+ and CD8+ effector T cell subpopulations can display regulatory potential characterized by expression of the prototypically anti-inflammatory cytokine IL-10. However, the underlying cellular mechanisms that regulate expression of IL-10 in different T cell subpopulations are not yet fully elucidated. We recently showed that TNF inhibitors (TNFi) promote IL-10 expression in human CD4+ T cells, including IL-17+ CD4+ T cells. Here, we further characterized the regulation of IL-10 expression via blockade of TNF signaling or other cytokine/co-stimulatory pathways, in human T cell subpopulations. Addition of the TNFi drug adalimumab to anti-CD3-stimulated human CD4+ T cell/monocyte cocultures led to increased percentages of IL-10+ cells in pro-inflammatory IL-17+, IFNγ+, TNFα+, GM-CSF+, and IL-4+ CD4+ T cell subpopulations. Conversely, exogenous TNFα strongly decreased IL-10+ cell frequencies. TNF blockade also regulated IL-10 expression in CD4+ T cells upon antigenic stimulation. Using time course experiments in whole peripheral blood mononuclear cell (PBMC) cultures, we show that TNF blockade maintained, rather than increased, IL-10+ cell frequencies in both CD4+ and CD8+ T cells following in vitro stimulation in a dose- and time-dependent manner. Blockade of IL-17, IFNγ, IL-6R, or CD80/CD86-mediated co-stimulation did not significantly regulate IL-10 expression within CD4+ or CD8+ T cell subpopulations. We show that TNF blockade acts directly on effector CD4+ T cells, in the absence of monocytes or CD4+ CD25highCD127low regulatory T cells and independently of IL-27, resulting in higher IL-10+ frequencies after 3 days in culture. IL-10/IL-10R blockade reduced the frequency of IL-10-expressing cells both in the presence and absence of TNF blockade. Addition of recombinant IL-10 alone was insufficient to drive an increase in IL-10+ CD4+ T cell frequencies in 3-day CD4+ T cell/monocyte cocultures, but resulted in increased IL-10 expression at later time points in whole PBMC cultures. Together, these data provide additional insights into the regulation of IL-10 expression in human T cells by TNF blockade. The maintenance of an IL-10+ phenotype across a broad range of effector T cell subsets may represent an underappreciated mechanism of action underlying this widely used therapeutic strategy.