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Fms-like tyrosine kinase 3 ligand controls formation of regulatory T cells in autoimmune arthritis.

Journal article
Authors Mattias Svensson
Sofia E M Andersson
Malin Erlandsson
Ing-Marie Jonsson
Anna-Karin H Ekwall
Karin Andersson
Anders Nilsson
Li Bian
Mikael Brisslert
Maria Bokarewa
Published in PloS one
Volume 8
Issue 1
Pages e54884
ISSN 1932-6203
Publication year 2013
Published at Institute of Medicine, Department of Rheumatology and Inflammation Research
Institute of Clinical Sciences, Department of Orthopaedics
Pages e54884
Language en
Links dx.doi.org/10.1371/journal.pone.005...
Keywords Animals, Arthritis, chemically induced, metabolism, Autoimmune Diseases, chemically induced, metabolism, Dendritic Cells, immunology, metabolism, pathology, Humans, Interleukin-6, immunology, metabolism, Membrane Proteins, genetics, metabolism, Mice, Serum Albumin, Bovine, toxicity, T-Lymphocytes, Regulatory, immunology, metabolism, pathology, Tumor Necrosis Factor-alpha, immunology, metabolism, fms-Like Tyrosine Kinase 3, metabolism
Subject categories Basic Medicine, Immunobiology

Abstract

Fms-like tyrosine kinase 3 ligand (Flt3L) is known as the primary differentiation and survival factor for dendritic cells (DCs). Furthermore, Flt3L is involved in the homeostatic feedback loop between DCs and regulatory T cell (Treg). We have previously shown that Flt3L accumulates in the synovial fluid in rheumatoid arthritis (RA) and that local exposure to Flt3L aggravates arthritis in mice, suggesting a possible involvement in RA pathogenesis. In the present study we investigated the role of Flt3L on DC populations, Tregs as well as inflammatory responses in experimental antigen-induced arthritis. Arthritis was induced in mBSA-immunized mice by local knee injection of mBSA and Flt3L was provided by daily intraperitoneal injections. Flow cytometry analysis of spleen and lymph nodes revealed an increased formation of DCs and subsequently Tregs in mice treated with Flt3L. Flt3L-treatment was also associated with a reduced production of mBSA specific antibodies and reduced levels of the pro-inflammatory cytokines IL-6 and TNF-α. Morphological evaluation of mBSA injected joints revealed reduced joint destruction in Flt3L treated mice. The role of DCs in mBSA arthritis was further challenged in an adoptive transfer experiment. Transfer of DCs in combination with T-cells from mBSA immunized mice, predisposed naïve recipients for arthritis and production of mBSA specific antibodies. We provide experimental evidence that Flt3L has potent immunoregulatory properties. Flt3L facilitates formation of Treg cells and by this mechanism reduces severity of antigen-induced arthritis in mice. We suggest that high systemic levels of Flt3L have potential to modulate autoreactivity and autoimmunity.

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