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Tumor-released autophagosomes induce IL-10-producing B cells with suppressive activity on T lymphocytes via TLR2-MyD88-NF-κB signal pathway.

ABSTRACT: Recent studies have shown that tumor cells can release autophagosomes, which transport a broad array of biologically active molecules with potential modulatory effects on immune cell functions. In this study, we aimed to investigate the role of tumor cells-released autophagosomes (i.e. TRAP) in regulating B cell differentiation and function. TRAPs from murine tumor cell lines were found to induce splenic B cells to differentiate into IL-10-producing regulatory B cells (Bregs) with a distinct phenotype of CD1d(+) CD5(+), which could potently inhibit CD8(+) and CD4(+) T cell responses in IL-10-depedent manner both in vitro and in vivo. Notably, adoptive transfer of TRAP-induced Bregs abrogated the immune response and antitumor effect induced by OVA-loaded DC vaccinations in E.G7-OVA-bearing mouse model. Mechanistic studies revealed that membrane-bound high-mobility group B1 (HMGB1) on the intact TRAPs was crucial for inducing Breg differentiation via the activation of TLR2-MyD88-NF-κB signal pathway in B cells. Moreover, TRAPs enriched from malignant effusions of cancer patients could induce human B cells to differentiate into IL-10-producing B cells with immunoregulatory functions, the frequency of which were positively correlated with the HMGB1 levels on TRAPs. Together, our findings have demonstrated that TRAPs promote the generation of IL-10(+) Bregs, which may contribute to the suppression of antitumor immunity.

SUBMITTER: Zhou M

PROVIDER: S-EPMC5006924 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The polymorphic membrane protein D (PmpD) is a highly conserved outer membrane protein which plays an important role in pathogenesis during Chlamydia psittaci infection. In this study, we evaluated the ability of the N-terminus of PmpD (PmpD-N) to modulate the functions of chicken macrophages and the signaling pathway(s) involved in PmpD-N-induced Toll-like receptors (TLRs), as well as interleukin (IL)-6 and IL-10 cytokine secretions. Thus, HD11 macrophages were treated with exogenous and intracellular PmpD-N of C. psittaci. The chlamydial growth was evaluated by enumeration of chlamydial loads in the infected macrophages. The phagocytic function of macrophages following PmpD-N treatment was detected by fluorescein-labeled Escherichia coli (E. coli). The concentration of nitric oxide (NO) secreted by HD11 macrophages was measured by the amount of NO2- in the culture supernatant using the Griess method. The cytokine secretions were assessed using multiplex cytokine ELISA kits. Expression levels of TLRs, myeloid differentiation factor 88 (MyD88), and nuclear factor kappa B (NF-κB) were analyzed by a Western blotting assay, as well as a luciferase assay, while NF-κB p65 nuclear translocation was assessed by confocal microscopy. The nuclear translocation of the transcription factor NF-κB was confirmed by evaluating its ability to combine with the corresponding promoter using the electrophoretic mobility shift assay (EMSA). After treatment with exogenous or endogenous PmpD-N, chlamydial loads and phagocytic functions were reduced significantly compared with those of the plasmid vector group, while NO secretions were reduced significantly compared with those of the lipopolysaccharide (LPS) treatment. Stimulation of HD11 cells with PmpD-N provoked the secretion of the Th2 cytokines, IL-6, and IL-10 and upregulated the expression of TLR2, TLR4, MyD88, and NF-κB. Furthermore, inhibition of TLR2, MyD88, and NF-κB in HD11 cells significantly decreased IL-6 and IL-10 cytokine levels, while NO production and phagocytosis increased significantly, strongly suggesting their involvement in PmpD-N-induced Th2 cytokine secretion and macrophage dysfunction. Our data indicate that C. psittaci PmpD-N inhibited macrophage functions by activating the Th2 immune response and the TLR2/MyD88/NF-κB signaling pathway.

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Tumor-released autophagosomes induce IL-10-producing B cells with suppressive activity on T lymphocytes via TLR2-MyD88-NF-κB signal pathway.

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