TNF-α blockade induces IL-10 expression in human CD4+ T cells.
IL-17+ CD4+ T (Th17) cells contribute to the pathogenesis of several human inflammatory diseases. Here we demonstrate that TNF inhibitor (TNFi) drugs induce the anti-inflammatory cytokine IL-10 in CD4+ T cells including IL-17+ CD4+ T cells. TNFi-mediated induction of IL-10 in IL-17+ CD4+ T cells is Treg-/Foxp3-independent, requires IL-10 and is overcome by IL-1β. TNFi-exposed IL-17+ CD4+ T cells are molecularly and functionally distinct, with a unique gene signature characterized by expression of IL10 and IKZF3 (encoding Aiolos). We show that Aiolos binds conserved regions in the IL10 locus in IL-17+ CD4+ T cells. Furthermore, IKZF3 and IL10 expression levels correlate in primary CD4+ T cells and Aiolos overexpression is sufficient to drive IL10 in these cells. Our data demonstrate that TNF-α blockade induces IL-10 in CD4+ T cells including Th17 cells and suggest a role for the transcription factor Aiolos in the regulation of IL-10 in CD4+ T cells.
Centre for Molecular & Cellular Biology of Inflammation (CMCBI), Division of Immunology, Infection and Inflammatory Disease, King's College London, SE1 1UL, UK.
Hayley G
HG
Evans
Centre for Molecular & Cellular Biology of Inflammation (CMCBI), Division of Immunology, Infection and Inflammatory Disease, King's College London, SE1 1UL, UK.
Urmas
U
Roostalu
Centre for Molecular & Cellular Biology of Inflammation (CMCBI), Division of Immunology, Infection and Inflammatory Disease, King's College London, SE1 1UL, UK.
Gina J
GJ
Walter
Centre for Molecular & Cellular Biology of Inflammation (CMCBI), Division of Immunology, Infection and Inflammatory Disease, King's College London, SE1 1UL, UK.
Nicola J
NJ
Gullick
Novo Nordisk A/S, Biopharmaceuticals Research Unit, Inflammation Biology, 2760 Måløv, Denmark.
Klaus S
KS
Frederiksen
Centre for Molecular & Cellular Biology of Inflammation (CMCBI), Division of Immunology, Infection and Inflammatory Disease, King's College London, SE1 1UL, UK.
Ceri A
CA
Roberts
Centre for Molecular & Cellular Biology of Inflammation (CMCBI), Division of Immunology, Infection and Inflammatory Disease, King's College London, SE1 1UL, UK.
Jonathan
J
Sumner
Division of Clinical Immunology and Rheumatology, Academic Medical Centre, Amsterdam, 1105 AZ, the Netherlands.
Dominique L
DL
Baeten
Novo Nordisk A/S, Biopharmaceuticals Research Unit, Inflammation Biology, 2760 Måløv, Denmark.
Jens G
JG
Gerwien
Centre for Molecular & Cellular Biology of Inflammation (CMCBI), Division of Immunology, Infection and Inflammatory Disease, King's College London, SE1 1UL, UK.|Academic Department of Rheumatology, SE1 1UL, King's College London, UK.
Andrew P
AP
Cope
Centre for Molecular & Cellular Biology of Inflammation (CMCBI), Division of Immunology, Infection and Inflammatory Disease, King's College London, SE1 1UL, UK.
Frederic
F
Geissmann
Department of Rheumatology, Guy's & St Thomas' NHS Trust, London, SE1 9RT, UK.
Bruce W
BW
Kirkham
Centre for Molecular & Cellular Biology of Inflammation (CMCBI), Division of Immunology, Infection and Inflammatory Disease, King's College London, SE1 1UL, UK.
Leonie S
LS
Taams
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D001483:Base Sequence; D016022:Case-Control Studies; D002417:Cattle; D002478:Cells, Cultured; D017124:Conserved Sequence; D004285:Dogs; D006801:Humans; D051740:Ikaros Transcription Factor / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D051381:Rats; D012689:Sequence Homology, Nucleic Acid; D058504:Th17 Cells / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D018501:Antirheumatic Agents; C106285:IKZF3 protein, human; C508609:IL10 protein, human; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D051740:Ikaros Transcription Factor