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

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.

Tumor microenvironment immunomodulation by nanoformulated TLR 7/8 agonist and PI3k delta inhibitor enhances therapeutic benefits of radiotherapy

“…Thus, we used depleting antibodies to assess tumor growth and survival of RT+Res:ID recipients compared to the same treatment in the animals deficient in either B cells, CD8 + or CD4 + T cells, or Gr1 + myeloid cells ( Fig. 6e ) [34]. Strikingly, the control of tumor growth was lost in RT+Res:ID-treated mice after depletion of either lymphoid (CD4 + and CD8 + T cells, B cells) or myeloid cells broadly, indicating an important role of these immune cells in the anti-tumor immune response.…”