Synovial Fibroblasts Selectively Suppress Th1 Cell Responses through IDO1-Mediated Tryptophan Catabolism

The development of rheumatoid arthritis (RA) is linked to functional changes in synovial fibroblasts (SF) and local infiltration of T lymphocytes. Fibroblasts possess the capacity to suppress T cell responses, although the molecular mechanisms of this suppression remain incompletely understood. In this study, we aimed to define the mechanisms by which noninflammatory SF modulate Th cell responses and to determine the immunosuppressive efficacy of RASF. Hence, the influence of SF from osteoarthritis or RA patients on total Th cells or different Th cell subsets of healthy donors was analyzed in vitro. We show that SF strongly suppressed the proliferation of Th cells and the secretion of IFN-γ in a cell contact–independent manner. In cocultures of SF and Th cells, tryptophan was completely depleted within a few days, resulting in eukaryotic initiation factor 2α phosphorylation, TCRζ-chain downregulation, and proliferation arrest. Blocking IDO1 activity completely restored Th cell proliferation, but not IFN-γ production. Interestingly, only the proliferation of Th1 cells, but not of Th2 or Th17 cells, was affected. Finally, RASF had a significantly lower IDO1 expression and a weaker Th cell suppressive capacity compared with osteoarthritis SF. We postulate that the suppression of Th cell growth by SF through tryptophan catabolism may play an important role in preventing inappropriate Th cell responses under normal conditions. However, expansion of Th17 cells that do not induce IDO1-mediated suppression and the reduced capacity of RASF to restrict Th cell proliferation through tryptophan metabolism may support the initiation and propagation of synovitis in RA patients.

[1]  C. Plass,et al.  Suppression of indoleamine-2,3-dioxygenase 1 expression by promoter hypermethylation in ER-positive breast cancer , 2017, Oncoimmunology.

[2]  S. Jung,et al.  Downregulation of Tryptophan-related Metabolomic Profile in Rheumatoid Arthritis Synovial Fluid , 2015, The Journal of Rheumatology.

[3]  H. Lorenz,et al.  Activated human B cells induce inflammatory fibroblasts with cartilage-destructive properties and become functionally suppressed in return , 2015, Annals of the rheumatic diseases.

[4]  D. Furst,et al.  Rheumatoid arthritis pathophysiology: update on emerging cytokine and cytokine-associated cell targets. , 2014, Rheumatology.

[5]  Eugenia G. Giannopoulou,et al.  Modulation of TNF-Induced Macrophage Polarization by Synovial Fibroblasts , 2014, The Journal of Immunology.

[6]  R. Gay,et al.  Inhibition of Spermidine/Spermine N1‐Acetyltransferase Activity: A New Therapeutic Concept in Rheumatoid Arthritis , 2014, Arthritis & rheumatology.

[7]  S. Akira,et al.  The enzyme Cyp26b1 mediates inhibition of mast cell activation by fibroblasts to maintain skin-barrier homeostasis. , 2014, Immunity.

[8]  D. Fox,et al.  T cell subsets and their role in the pathogenesis of rheumatic disease , 2014, Current opinion in rheumatology.

[9]  P. Miossec,et al.  Interleukin 17 contributes to the chronicity of inflammatory diseases such as rheumatoid arthritis , 2014, European journal of immunology.

[10]  E. Lubberts,et al.  Synovial Fibroblasts Directly Induce Th17 Pathogenicity via the Cyclooxygenase/Prostaglandin E2 Pathway, Independent of IL-23 , 2013, The Journal of Immunology.

[11]  D. Munn,et al.  Indoleamine 2,3 dioxygenase and metabolic control of immune responses. , 2013, Trends in immunology.

[12]  P. Zhu,et al.  Functional niche of inflamed synovium for Th17-cell expansion and activation in rheumatoid arthritis: implication to clinical therapeutics. , 2012, Autoimmunity reviews.

[13]  Yufang Shi,et al.  How mesenchymal stem cells interact with tissue immune responses. , 2012, Trends in immunology.

[14]  M. Weller,et al.  An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor , 2011, Nature.

[15]  V. Kindler,et al.  Human Bone Marrow Stromal Cells and Skin Fibroblasts Inhibit Natural Killer Cell Proliferation and Cytotoxic Activity , 2011, Cell transplantation.

[16]  M. Kamal,et al.  Serum and synovial fluid levels of interleukin-17 in correlation with disease activity in patients with RA , 2011, Clinical Rheumatology.

[17]  M. Lai,et al.  Amelioration of rat collagen-induced arthritis through CD4+ T cells apoptosis and synovial interleukin-17 reduction by indoleamine 2,3-dioxygenase gene therapy. , 2011, Human gene therapy.

[18]  A. Skapenko,et al.  Role of Th17 cells in human autoimmune arthritis. , 2010, Arthritis and rheumatism.

[19]  A. Silman,et al.  UvA-DARE (Digital Academic Repository) 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative Aletaha, , 2010 .

[20]  A. Silman,et al.  Rheumatoid arthritis classifi cation criteria : an American College of Rheumatology / European League Against Rheumatism collaborative initiative , 2010 .

[21]  B. Larijani,et al.  Local Expression of Indoleamine 2,3 Dioxygenase in Syngeneic Fibroblasts Significantly Prolongs Survival of an Engineered Three-Dimensional Islet Allograft , 2010, Diabetes.

[22]  L. Casteilla,et al.  Human Fibroblasts Share Immunosuppressive Properties with Bone Marrow Mesenchymal Stem Cells , 2010, Journal of Clinical Immunology.

[23]  G. Firestein,et al.  Fibroblast‐like synoviocytes: key effector cells in rheumatoid arthritis , 2010, Immunological reviews.

[24]  R. Gay,et al.  DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. , 2009, Arthritis and rheumatism.

[25]  B. Baban,et al.  IDO Activates Regulatory T Cells and Blocks Their Conversion into Th17-Like T Cells1 , 2009, The Journal of Immunology.

[26]  D. Essex,et al.  Indoleamine 2,3 dioxygenase-mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen-induced arthritis. , 2009, Arthritis and rheumatism.

[27]  M. Weller,et al.  Toll‐Like Receptor Engagement Enhances the Immunosuppressive Properties of Human Bone Marrow‐Derived Mesenchymal Stem Cells by Inducing Indoleamine‐2,3‐dioxygenase‐1 via Interferon‐β and Protein Kinase R , 2009, Stem cells.

[28]  I. Pinchuk,et al.  PD-1 ligand expression by human colonic myofibroblasts/fibroblasts regulates CD4+ T-cell activity. , 2008, Gastroenterology.

[29]  A. Mandelin,et al.  TH-17 cells in rheumatoid arthritis , 2008, Arthritis research & therapy.

[30]  S. Chevalier,et al.  Chronically Inflamed Human Tissues Are Infiltrated by Highly Differentiated Th17 Lymphocytes , 2008, The Journal of Immunology.

[31]  V. Duronio,et al.  Differential immunosuppressive effect of indoleamine 2,3-dioxygenase (IDO) on primary human CD4+ and CD8+ T cells , 2008, Molecular and Cellular Biochemistry.

[32]  A. Cope,et al.  The Antiproliferative Effect of Mesenchymal Stem Cells Is a Fundamental Property Shared by All Stromal Cells1 , 2007, The Journal of Immunology.

[33]  A. Cope,et al.  The central role of T cells in rheumatoid arthritis. , 2007, Clinical and experimental rheumatology.

[34]  M. Haniffa,et al.  Adult Human Fibroblasts Are Potent Immunoregulatory Cells and Functionally Equivalent to Mesenchymal Stem Cells1 , 2007, The Journal of Immunology.

[35]  W. Wick,et al.  Tryptophan degradation in autoimmune diseases , 2007, Cellular and Molecular Life Sciences.

[36]  T. Glant,et al.  Inhibition of indoleamine 2,3-dioxygenase-mediated tryptophan catabolism accelerates collagen-induced arthritis in mice , 2007, Arthritis research & therapy.

[37]  D. Fox,et al.  Cells of the synovium in rheumatoid arthritis. T lymphocytes , 2007, Arthritis research & therapy.

[38]  Yuan Wang,et al.  Synovial Autoreactive T Cells in Rheumatoid Arthritis Resist IDO-Mediated Inhibition1 , 2006, The Journal of Immunology.

[39]  T. Šarić,et al.  CD25 and indoleamine 2,3-dioxygenase are up-regulated by prostaglandin E2 and expressed by tumor-associated dendritic cells in vivo: additional mechanisms of T-cell inhibition. , 2006, Blood.

[40]  J. Lord,et al.  Differential survival of leukocyte subsets mediated by synovial, bone marrow, and skin fibroblasts: site-specific versus activation-dependent survival of T cells and neutrophils. , 2006, Arthritis and rheumatism.

[41]  U. Grohmann,et al.  The Combined Effects of Tryptophan Starvation and Tryptophan Catabolites Down-Regulate T Cell Receptor ζ-Chain and Induce a Regulatory Phenotype in Naive T Cells1 , 2006, The Journal of Immunology.

[42]  P. Lipsky,et al.  Association of the IL4R single-nucleotide polymorphism I50V with rapidly erosive rheumatoid arthritis. , 2006, Arthritis and rheumatism.

[43]  M. Albert,et al.  A two-step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendritic-cell maturation. , 2005, Blood.

[44]  B. Baban,et al.  GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. , 2005, Immunity.

[45]  W. B. van den Berg,et al.  The role of T cell interleukin-17 in conducting destructive arthritis: lessons from animal models , 2004, Arthritis research & therapy.

[46]  S. Nakae,et al.  Suppression of Immune Induction of Collagen-Induced Arthritis in IL-17-Deficient Mice 1 , 2003, The Journal of Immunology.

[47]  R. Paules,et al.  An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. , 2003, Molecular cell.

[48]  J. Lord,et al.  Fibroblasts regulate the switch from acute resolving to chronic persistent inflammation. , 2001, Trends in immunology.

[49]  J. Banchereau,et al.  IL-6 switches the differentiation of monocytes from dendritic cells to macrophages , 2000, Nature Immunology.

[50]  P. Lipsky,et al.  Altered memory T cell differentiation in patients with early rheumatoid arthritis. , 1999, Journal of immunology.

[51]  Y. Shimabukuro,et al.  Interferon-gamma-dependent immunosuppressive effects of human gingival fibroblasts. , 1992, Immunology.

[52]  N. Bottini,et al.  Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors , 2013, Nature Reviews Rheumatology.

[53]  Xiaoyue Lin,et al.  Local expression of indoleamine 2,3-dioxygenase protects engraftment of xenogeneic skin substitute. , 2006, The Journal of investigative dermatology.