title: Inhibition of TNF receptor signaling by anti-TNFα biologicals primes naïve CD4(+) T cells towards IL-10(+) T cells with a regulatory phenotype and function.
abstract: TNFα is a potent pro-inflammatory cytokine playing a pivotal role in several autoimmune diseases. Little is known about the mechanism of TNFα blocking agents on naïve T cell differentiation. Here, we report that neutralizing TNFα during priming of naïve CD4(+) T cells by dendritic cells favors development of IL-10(+) T helper cells. TNFα counteracts IL-10(+) T cell priming mainly via TNFRI receptor signaling. While initial T cell activation was not affected, neutralization of TNFα negatively affected sustained T cell differentiation in later stages of T cell priming. Whole genome gene expression analysis revealed an extended regulatory gene profile for anti-TNFα-treated T cells. Indeed, neutralizing TNFα during naïve T cell priming enhanced the suppressive function of anti-TNFα-treated T cells. Taken together, inhibition of TNFα-TNFR interaction shifts the balance of Th cell differentiation towards IL-10 expressing suppressive T cells, which may be one of the beneficial mechanisms in TNFα blocking therapies.
authors.affiliation: Department of Immunopathology, Sanquin Blood Supply, Division Research and Landsteiner Laboratory, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Martine A
authors.initials: MA
authors.lastname: Boks
authors.affiliation: Department of Immunopathology, Sanquin Blood Supply, Division Research and Landsteiner Laboratory, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Judith R
authors.initials: JR
authors.lastname: Kager-Groenland
authors.affiliation: Department of Immunopathology, Sanquin Blood Supply, Division Research and Landsteiner Laboratory, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Mousset
authors.affiliation: Department of Immunopathology, Sanquin Blood Supply, Division Research and Landsteiner Laboratory, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: S Marieke
authors.initials: SM
authors.lastname: van Ham
authors.affiliation: Department of Immunopathology, Sanquin Blood Supply, Division Research and Landsteiner Laboratory, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: a.tenbrinke@sanquin.nl.
authors.forename: Anja
authors.initials: A
authors.lastname: ten Brinke
mesh_terms: D000068879:Adalimumab; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; C508609:IL10 protein, human; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000068879:Adalimumab
keywords: Anti-TNFα therapy; IL-10; Regulatory T cells; T cell polarization; TNF receptor