Enriched CD141+ DCs in the joint are transcriptionally distinct, activated, and contribute to joint pathogenesis.

CD141+ DC are implicated in antiviral and antitumor immunity. However, mechanisticstudies in autoimmune disease are limited. This is the first study to our knowledgeexamining CD141+ DC in autoimmune disease, specifically inflammatory arthritis (IA). Weidentified significant enrichment of CD141+ DC in the inflamed synovial joint, which weretranscriptionally distinct from IA and healthy control (HC) blood CD141+ DC andsignificantly more activated, and they exhibited increased responsiveness to TLR3.Synovial CD141+ DC represent a bone fide CD141+ DC population that is distinct fromCD1c+ DC. Synovial CD141+ DC induced higher levels of CD4+ and CD8+ T cell activationcompared with their peripheral blood counterparts, as made evident by expression of IFN-g,TNF-a, and granulocyte-macrophage CSF (GMCSF). Autologous synovial CD141+ DCcocultures also induce higher levels of these cytokines, further highlighting their contributionto synovial inflammation. Synovial CD141+ DC?T cell interactions had the ability to furtheractivate synovial fibroblasts, inducing adhesive and invasive pathogenic mechanisms.Furthermore, we identify a mechanism in which synovial CD141+ DC are activated, vialigation of the hypoxia-inducible immune-amplification receptor TREM-1, which increasedsynovial CD141+ DC activation, migratory capacity, and proinflammatory cytokines. Thus,synovial CD141+ DC display unique mechanistic and transcriptomic signatures, which aredistinguishable from blood CD141+ DC and can contribute to synovial joint inflammation