Plasmacytoid Dendritic Cells Enhance T-Independent B Cell Response through a p38 MAPK-STAT1 Axis

Hsin Hsiang Chen, Ya Ru Yu, Yu Ling Hsiao, Shun Hua Chen, Chien Kuo Lee

Research output: Contribution to journalArticlepeer-review

Abstract

TLR 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.

Original languageEnglish
Pages (from-to)576-590
Number of pages15
JournalJournal of Immunology
Volume211
Issue number4
DOIs
Publication statusPublished - 2023 Aug

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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