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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02068

Matured tolerogenic dendritic cells effectively inhibit autoantigen specific CD4+ T cells in a murine arthritis model

  • 1Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Netherlands
  • 2Institute of Cellular Medicine, Newcastle University, United Kingdom
  • 3Faculty of Veterinary medicine, Utrecht University, Department of Clinical Sciences of Companion Animals, Utrecht University, Netherlands

Tolerogenic dendritic cells (tolDCs) are a promising treatment modality for diseases caused by a breach in immune tolerance, such as rheumatoid arthritis. Current medication for these diseases is directed towards symptom suppression but no real cure is available yet. TolDC-based therapy aims to restore immune tolerance in an antigen-specific manner. Here we used a mouse model to address two major questions: i) is a maturation stimulus needed for tolDC function in vitro and in vivo and is maturation required for functioning in experimental arthritis and ii) can tolDCs modulate CD4+ T cell responses? To answer these questions, we compared matured and immature dexamethasone/vitamin D3-generated tolDCs in vitro. Subsequently, we co-transferred these tolDCs with naïve or effector CD4+ T cells to study the characteristics of transferred T cells after three days with flow cytometry and Luminex multiplex assays. In addition, we tested the suppressive capabilities of tolDCs in an experimental arthritis model. We found that tolDCs cannot only modulate naïve CD4+ T cell responses as shown by fewer proliferated and activated CD4+ T cells in vivo, but also effector CD4+ T cells. In addition, Treg expansions were seen in the proliferating cell population in the presence of tolDCs. Furthermore, we show that administered tolDCs are capable to inhibit arthritis in the proteoglycan-induced arthritis model. However, a maturation stimulus is needed for tolDCs to manifest this tolerizing function in an inflammatory environment. Our data will be instrumental for optimization of future tolDC therapies for autoimmune diseases.

Keywords: Tolerogenic dendritic cell (tolDC), Rheumathoid arthritis, CD4 T cells +, Immune Tolerance, Immune Modulation

Received: 10 Dec 2018; Accepted: 15 Aug 2019.

Edited by:

Djordje Miljkovic, Institute for Biological Research Sinisa Stankovic, University of Belgrade, Serbia

Reviewed by:

Bruce M. Hall, University of New South Wales, Australia
Nemanja Jovicic, University of Kragujevac, Serbia  

Copyright: © 2019 Jansen, Spiering, Ludwig, Van Eden, Hilkens and Broere. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Femke Broere, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, 3584, Netherlands, Netherlands, f.broere@uu.nl