Chen, Hsin-HsiangHsin-HsiangChenYu, Ya-RuYa-RuYuHsiao, Yu-LingYu-LingHsiaoChen, Shun-HuaShun-HuaChenCHIEN-KUO LEE2024-03-272024-03-272023-08-1500221767https://scholars.lib.ntu.edu.tw/handle/123456789/641465TLR signaling in B cells triggers their activation and differentiation independent of help from T cells. Plasmacytoid dendritic cells (pDCs) cooperate with B cells to boost TLR-stimulated T-independent humoral immunity; however, the molecular mechanisms remain elusive. In this study, we demonstrate that in the mouse system, the adjuvant effects of pDCs also occurred following challenge with pathogens and that follicular (FO) B cells were more sensitive to pDC-induced enhancement than were marginal zone (MZ) B cells. Moreover, pDCs migrated to the FO zones and interacted with FO B cells upon stimulation in vivo. CXCL10, a ligand for CXCR3 expressed on pDCs, was superinduced in the coculture system and facilitated the cooperative activation of B cells. Moreover, pDCs also promoted TLR-stimulated autoantibody production in FO B and MZ B cells. Ingenuity Pathway Analysis and gene set enrichment analysis revealed that type I IFN (IFN-I)-mediated JAK-STAT and Ras-MAPK pathways were highly enriched in R848-stimulated B cells cocultured with pDCs compared with B cells alone. Whereas IFN-I receptor 1 deficiency reduced pDC-enhanced B cell responses, STAT1 deficiency displayed a more pronounced defect. One of the STAT1-dependent but IFN-I-independent mechanisms was TLR-induced STAT1-S727 phosphorylation by p38 MAPK. Serine 727 to alanine mutation attenuated the synergism between pDCs and B cells. In conclusion, we uncover a molecular mechanism for pDC-enhanced B cell response and define a crucial role of the IFN-I/TLR-mediated signaling pathway through a p38 MAPK-STAT1 axis in controlling T-independent humoral immunity and providing a novel therapeutic target for treating autoimmune diseases.enjournal article10.4049/jimmunol.2200210374279822-s2.0-85167470569https://api.elsevier.com/content/abstract/scopus_id/85167470569