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

CD141(+) 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 DC1c(+) 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-gamma TNF-alpha, 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.