Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model

This report shows that interleukin (IL) 17–producing T helper type 17 (Th17) cells predominantly express CC chemokine receptor (CCR) 6 in an animal model of rheumatoid arthritis (RA). Th17 cells induced in vivo in normal mice via homeostatic proliferation similarly express CCR6, whereas those inducible in vitro by transforming growth factor β and IL-6 additionally need IL-1 and neutralization of interferon (IFN) γ and IL-4 for CCR6 expression. Forced expression of RORγt, a key transcription factor for Th17 cell differentiation, induces not only IL-17 but also CCR6 in naive T cells. Furthermore, Th17 cells produce CCL20, the known ligand for CCR6. Synoviocytes from arthritic joints of mice and humans also produce a large amount of CCL20, with a significant correlation (P = 0.014) between the amounts of IL-17 and CCL20 in RA joints. The CCL20 production by synoviocytes is augmented in vitro by IL-1β, IL-17, or tumor necrosis factor α, and is suppressed by IFN-γ or IL-4. Administration of blocking anti-CCR6 monoclonal antibody substantially inhibits mouse arthritis. Thus, the joint cytokine milieu formed by T cells and synovial cells controls the production of CCL20 and, consequently, the recruitment of CCR6+ arthritogenic Th17 cells to the inflamed joints. These results indicate that CCR6 expression contributes to Th17 cell function in autoimmune disease, especially in autoimmune arthritis such as RA.

[1]  M. Kleinewietfeld,et al.  CCR6 expression defines regulatory effector/memory-like cells within the CD25(+)CD4+ T-cell subset. , 2005, Blood.

[2]  T. Matsui,et al.  Selective recruitment of CCR6‐expressing cells by increased production of MIP‐3α in rheumatoid arthritis , 2001, Clinical and experimental immunology.

[3]  Satoshi Tanaka,et al.  T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis , 2007, The Journal of experimental medicine.

[4]  T. Nomura,et al.  Distinct contribution of IL-6, TNF-alpha, IL-1, and IL-10 to T cell-mediated spontaneous autoimmune arthritis in mice. , 2004, The Journal of clinical investigation.

[5]  R. Rabin,et al.  CC-Chemokine Receptor 6 Is Expressed on Diverse Memory Subsets of T Cells and Determines Responsiveness to Macrophage Inflammatory Protein 3α , 1999, The Journal of Immunology.

[6]  T. Mcclanahan,et al.  IL-23 drives a pathogenic T cell population that induces autoimmune inflammation , 2005, The Journal of experimental medicine.

[7]  D. Jarrossay,et al.  Surface phenotype and antigenic specificity of human interleukin 17–producing T helper memory cells , 2007, Nature Immunology.

[8]  K. Mills,et al.  A crucial role for interleukin (IL)-1 in the induction of IL-17–producing T cells that mediate autoimmune encephalomyelitis , 2006, The Journal of experimental medicine.

[9]  R. Rabin,et al.  CC-chemokine receptor 6 is expressed on diverse memory subsets of T cells and determines responsiveness to macrophage inflammatory protein 3 alpha. , 1999, Journal of immunology.

[10]  P. Valdez,et al.  Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis , 2007, Nature.

[11]  Ying Wang,et al.  A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17 , 2005, Nature Immunology.

[12]  J. Sirard,et al.  Dendritic cells rapidly recruited into epithelial tissues via CCR6/CCL20 are responsible for CD8+ T cell crosspriming in vivo. , 2006, Immunity.

[13]  D. Littman,et al.  The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells , 2006, Cell.

[14]  S. Sakaguchi.  Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self , 2005, Nature Immunology.

[15]  B. Serafini,et al.  Astrocytes are the major intracerebral source of macrophage inflammatory protein‐3α/CCL20 in relapsing experimental autoimmune encephalomyelitis and in vitro , 2003, Glia.

[16]  S. Nakae,et al.  IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[17]  R. J. Hocking,et al.  TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. , 2006, Immunity.

[18]  R. D. Hatton,et al.  Transforming growth factor-beta induces development of the T(H)17 lineage. , 2006, Nature.

[19]  S. McColl,et al.  A Role for Macrophage Inflammatory Protein-3α/CC Chemokine Ligand 20 in Immune Priming During T Cell-Mediated Inflammation of the Central Nervous System1 , 2003, The Journal of Immunology.

[20]  B. Serafini,et al.  Intracerebral recruitment and maturation of dendritic cells in the onset and progression of experimental autoimmune encephalomyelitis. , 2000, The American journal of pathology.

[21]  Pawan Kumar,et al.  Role of Macrophage Inflammatory Protein-3α and Its Ligand CCR6 in Rheumatoid Arthritis , 2003, Laboratory Investigation.

[22]  H. Weiner,et al.  Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells , 2006, Nature.

[23]  C. Werning.  [Rheumatoid arthritis]. , 1983, Medizinische Monatsschrift fur Pharmazeuten.

[24]  C. Caux,et al.  Macrophage Inflammatory Protein 3α Is Expressed at Inflamed Epithelial Surfaces and Is the Most Potent Chemokine Known in Attracting Langerhans Cell Precursors , 2000, The Journal of experimental medicine.

[25]  T. Martin,et al.  IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. , 1999, The Journal of clinical investigation.

[26]  S. Akira,et al.  A role for fungal β-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice , 2005, The Journal of experimental medicine.

[27]  S. Sakaguchi,et al.  Control of immune responses by antigen-specific regulatory T cells expressing the folate receptor. , 2007, Immunity.

[28]  E. Kriehuber,et al.  Macrophage Inflammatory Protein 3α Is Involved in the Constitutive Trafficking of Epidermal Langerhans Cells , 1999, The Journal of experimental medicine.

[29]  R. D. Hatton,et al.  Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages , 2005, Nature Immunology.

[30]  A. Iwasaki,et al.  Localization of Distinct Peyer's Patch Dendritic Cell Subsets and Their Recruitment by Chemokines Macrophage Inflammatory Protein (Mip)-3α, Mip-3β, and Secondary Lymphoid Organ Chemokine , 2000, The Journal of experimental medicine.

[31]  T. Nomura,et al.  Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice , 2003, Nature.