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

Front. Immunol. | doi: 10.3389/fimmu.2019.01504

Human memory Th17 cell populations change into anti-inflammatory cells with regulatory capacity upon exposure to active vitamin D

  • 1Department of Rheumatology, Erasmus Medical Center, Erasmus University Rotterdam, Netherlands
  • 2Department of Internal Medicine, Erasmus Medical Center, Erasmus University Rotterdam, Netherlands
  • 3Ziekenhuis Groep Twente, Netherlands

Autoimmune diseases are characterized by an aberrantly activated immune system, resulting in tissue damage and functional disability in patients. An important therapeutic goal is to restore the deregulated immunological balance between pro- and anti-inflammatory T cells. This imbalance is illustrated by elevated levels and activity of memory Th17 cell populations, such as Th17, Th1/Th17 and Th17.1 cells, in various autoimmune diseases. These cells are characterized by the chemokine receptor CCR6, RORC expression and production of IL-17A, IFNγ and TNFα. Using rheumatoid arthritis (RA) as a model autoimmune disease, we here demonstrate that pro-inflammatory memory CCR6+ Th cells can switch into anti-inflammatory cells with regulatory capacity using the active vitamin D metabolite 1,25(OH)2D3. Memory CCR6+ Th cells, excluding Tregs, were sorted from healthy controls or treatment-naïve patients with early rheumatoid arthritis (RA) and cultured with or without 1,25(OH)2D3. Treatment with 1,25(OH)2D3 inhibited pro-inflammatory cytokines such as IL-17A, IL-17F, IL-22 and IFNγ in memory CCR6+ Th cells from both healthy controls and RA patients. This was accompanied by induction of anti-inflammatory factors, including IL-10 and CTLA4. Interestingly, these formerly pathogenic cells suppressed proliferation of autologous CD3+ T cells similar to classical Tregs. Importantly, the modulated memory cells still migrated towards the site of inflammation, modelled by RA synovial fluid, and retained their suppressive capacity in this environment. These data show the potential to reset the pathogenic profile of human memory Th cells into non-pathogenic cells with regulatory capacity.

Keywords: Th17, Vitamin D, autoimmune disease, Immune Regulation, Treg

Received: 05 Oct 2018; Accepted: 17 Jun 2019.

Edited by:

Nadia Caccamo, University of Palermo, Italy

Reviewed by:

Christoph Wülfing, University of Bristol, United Kingdom
Bhalchandra Mirlekar, UNC Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, United States  

Copyright: © 2019 Dankers, Davelaar, Van Hamburg, van de Peppel, Colin and Lubberts. 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: Dr. Erik Lubberts, Department of Rheumatology, Erasmus Medical Center, Erasmus University Rotterdam, Rotterdam, Netherlands, e.lubberts@erasmusmc.nl