Enriched Cd141+ DCs in the joint are transcriptionally distinct, activated, and contribute to joint pathogenesis

JCI Insight. 2018 Dec 6;3(23):e95228. doi: 10.1172/jci.insight.95228.

Abstract

CD141+ DC are implicated in antiviral and antitumor immunity. However, mechanistic studies in autoimmune disease are limited. This is the first study to our knowledge examining CD141+ DC in autoimmune disease, specifically inflammatory arthritis (IA). We identified significant enrichment of CD141+ DC in the inflamed synovial joint, which were transcriptionally distinct from IA and healthy control (HC) blood CD141+ DC and significantly more activated, and they exhibited increased responsiveness to TLR3. Synovial CD141+ DC represent a bone fide CD141+ DC population that is distinct from CD1c+ DC. Synovial CD141+ DC induced higher levels of CD4+ and CD8+ T cell activation compared with their peripheral blood counterparts, as made evident by expression of IFN-γ, TNF-α, and granulocyte-macrophage CSF (GMCSF). Autologous synovial CD141+ DC cocultures also induce higher levels of these cytokines, further highlighting their contribution to synovial inflammation. Synovial CD141+ DC-T cell interactions had the ability to further activate synovial fibroblasts, inducing adhesive and invasive pathogenic mechanisms. Furthermore, we identify a mechanism in which synovial CD141+ DC are activated, via ligation of the hypoxia-inducible immune-amplification receptor TREM-1, which increased synovial CD141+ DC activation, migratory capacity, and proinflammatory cytokines. Thus, synovial CD141+ DC display unique mechanistic and transcriptomic signatures, which are distinguishable from blood CD141+ DC and can contribute to synovial joint inflammation.

Keywords: Autoimmunity; Dendritic cells; Immunology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antigens, CD1
  • Antigens, Surface / blood
  • Antigens, Surface / immunology*
  • Antigens, Surface / metabolism*
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / pathology
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / metabolism
  • CD4-Positive T-Lymphocytes
  • CD8-Positive T-Lymphocytes
  • Cytokines / metabolism
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism*
  • Female
  • Glycoproteins
  • Humans
  • Inflammation
  • Interferon-gamma / metabolism
  • Joint Diseases / immunology*
  • Lymphocyte Activation
  • Macrophages / metabolism
  • Male
  • Middle Aged
  • Receptors, Immunologic
  • Synovial Membrane
  • Toll-Like Receptor 3 / metabolism
  • Transcriptome
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antigens, CD1
  • Antigens, Surface
  • CD1C protein, human
  • Cytokines
  • Glycoproteins
  • Receptors, Immunologic
  • TLR3 protein, human
  • Toll-Like Receptor 3
  • Tumor Necrosis Factor-alpha
  • blood dendritic cell antigen 3, human
  • Interferon-gamma