Functionally Mature CD1c + Dendritic Cells Preferentially Accumulate in the Inflammatory Arthritis Synovium.

Objective: To examine the role of synovial CD1c ⁺ DCs in patients with Inflammatory Arthritis (IA) with a specific focus on the transcriptional and maturation signatures that govern their function.
Methods: RNA sequencing was performed on healthy control (HC) peripheral blood (PB), IA PB, and IA synovial fluid (SF) CD1c ⁺ DCs. Multiparametric flow-cytometry and SPICE analysis were used to examine site [SF and Synovial Tissue (ST) CD1c+DCs] and disease specific characteristics of CD1c ⁺ DCs, while functional assays such as antigen processing, activation, and MMP production were also performed.
Results: Increased frequency of CD1c ⁺ DCs (p<0.01) with a concomitant increase in CD80, CCR7 (p<0.01), and CXCR3 (p<0.05) expression was identified in IA PB compared to HC PB. Enrichment of CD1c ⁺ DCs was identified in IA synovial tissue (ST) (p<0.01) and IA SF (p<0.0001) compared to IA PB, while RNAseq revealed distinct transcriptional variation between PB and SF CD1c ⁺ DCs. Flow cytometry revealed increased expression of CD83, CD80, PD-L1, and BTLA (all p<0.05) in IA SF CD1c ⁺ DCs compared to PB, while SPICE identified synovial cells with unique co-expression patterns, expressing multiple DC maturation markers simultaneously. Functionally, synovial CD1c ⁺ DCs are hyper-responsive to TLR7/8 ligation (p<0.05), have decreased antigen processing capacity (p=0.07), and display dysregulated production of MMPs. Finally, examination of both synovial CD1c ⁺ DCs and synovial CD141 ⁺ DCs revealed distinct maturation and transcriptomic profiles.
Conclusion: Synovial CD1c ⁺ DCs accumulate in the inflamed IA synovium in a variety of distinct poly-maturational states, distinguishing them transcriptionally and functionally from CD1c ⁺ DCs in the periphery and synovial CD141 ⁺ DCs.
Competing Interests: VP and SN were employed by Janssen Research & Development. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2021 Canavan, Marzaioli, Bhargava, Nagpal, Gallagher, Hurson, Mullan, Veale and Fearon.)