Deciphering the role of cDC2s in Sjogren’s Syndrome: transcriptomic profile reveals altered antigen processing and uptake associated with IFN-signatures and autoimmunity

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by lymphocytic infiltration of the exocrine glands. Conventional dendritic cells (cDCs)-2 play a critical role in T and B cell activation, leading to germinal centre formation and autoantibody production. To understand the mechanisms underlying cDC2 dysregulation in pSS we performed RNA-sequencing analysis and functional validation on circulating cDC2s from pSS, non-Sjögren’s sicca (nSS) patients and healthy controls (HC). Two independent cohorts were established to identify reproducible dysregulated signatures, which included the interferon (IFN), toll-like receptors (TLR) signaling and antigen processing and presentation pathways. We confirm by flow cytometry that pSS-cDC2s were less efficient to degrade BSA but more efficient to uptake BSA both linked with the presence of anti-SSA antibodies. As the majority of the SSA+ pSS patients exhibit an IFN-signature, we tested whether IFNα priming would influence cDC2s antigen-uptake and processing. IFNα priming increased cDC2s uptake capacity, but not antigen processing. Additionally, pSS-cDC2s showed an increased uptake capacity of apoptotic salivary gland epithelial cells. Finally, pSS-cDC2s increased the proliferation of HC CD4+ T cells and the expression of CXCR3 and CXCR5 on the proliferating HC CD4+ T cells, contributing to T cell migration into the inflamed salivary glands. Here we provide the first in-depth molecular characterization of pSS-cDC2s and show that the transcriptomic and functional alterations observed in pSS-cDC2s are linked to IFN-signature. In view of its role in pSS immunopathology, delineating the molecular networks that drive cDC2s holds promise for targeting these cells in pSS. RNA-sequencing of pheripheral blood isolated cDC2s from patients with primary Sjögren’s syndrome (pSS; n=23), non-Sjögren’s sicca (nSS; n=15), and healthy controls (HC; n=18).