TLR Agonists Selectively Promote Terminal Plasma Cell Differentiation of B Cell Subsets Specialized in Thymus-Independent Responses

Institut National de la Santé et de la Recherche Médicale Unité 851, IFR128 Biosciences Lyon-Gerland, 21 Avenue Tony Garnier, Lyon, France.
The Journal of Immunology (Impact Factor: 4.92). 07/2007; 178(12):7779-86. DOI: 10.4049/jimmunol.178.12.7779
Source: PubMed


Naive murine B cells are known to proliferate and differentiate in response to LPS or CpG, which bind to TLR4 and TLR9, respectively. However, the naive murine B cell compartment is heterogeneous and comprises four different B cell subsets: B-1a, B-1b, marginal zone (MZ), and follicular (FO) B cells. B-1a, B-1b, and MZ B cells are specialized in the response to thymus-independent Ag, and FO B cells are involved in the response to thymus-dependent Ag. This study was undertaken to compare those four naive B cell subsets for their responses to TLR agonists. Quantitative RT-PCR analysis revealed that expression of TLR transcripts differs quantitatively but not qualitatively from one subset to the other. All TLR agonists, with the exception of flagellin and poly(I:C), stimulate B cell proliferation whatever the subset considered. However, TLR ligation leads to massive differentiation of B-1 and MZ B cells into mature plasma cells (PC) but only marginally promotes PC differentiation of FO B cells. Moreover, TLR stimulation strongly up-regulates expression of Blimp-1 and XBP-1(S), two transcription factors known to be instrumental in PC differentiation, in B-1 and MZ B cells but not in FO B cells. Altogether, our findings suggest that B-1 and MZ B cells are poised to PC differentiation in response to the microbial environment and that TLR agonists can be instrumental in stimulating Ab-mediated innate immune protection during microbial infections.

3 Reads
  • Source
    • "Our result also confirmed this abnormality (Figure S4). MZ B cells are programmed for efficient differentiation into mature plasma cells with the ability to secrete massive quantities of IgM in response to TLR agonists such as LPS [42]. In addition, MZ B cells have an enhanced secretory apparatus [43] and lower activation thresholds [44]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Systemic lupus erythematosus (SLE) is characterized by prominent autoinflammatory tissue damage associated with impaired removal of dying cells and DNA. Self DNA-containing immune complexes are able to activate both innate and adaptive immune responses and play an important role in the maintenance and exacerbation of autoimmunity in SLE. In this study, we used DNA from lymphocytes that have undergone activation-induced cell death (ALD-DNA) and analyzed its role on the activation and differentiation of B cells from normal BALB/c mice as well as lupus-prone MRL+/+ and MRL/lpr mice. We found that ALD-DNA directly increased the expression of costimulatory molecules and the survival of naïve B cells in vitro. Although ALD-DNA alone had little effect on the proliferation of naïve B cells, it enhanced LPS-activated B cell proliferation in vitro and in vivo. In addition, ALD-DNA increased plasma cell numbers and IgG production in LPS-stimulated cultures of naïve B cells, in part via enhancing IL-6 production. Importantly, B cells from lupus mice were hyperresponsive to ALD-DNA and/or LPS relative to normal control B cells in terminal plasma cell differentiation, as evidenced by increases in CD138+ cell numbers, IgM production, and mRNA levels of B lymphocyte-induced maturation protein-1 (Blimp-1) and the X-box binding protein 1 (XBP1). Furthermore, ALD-DNA enhanced CD40-activated naïve B cell proliferation. Collectively, these data indicate that self DNA can serve as a DAMP (damage-associated molecular pattern) that cooperates with signals from both innate and adaptive immunity to promote polyclonal B cell activation, a common characteristic of autoimmune diseases.
    PLoS ONE 10/2014; 9(10):e109095. DOI:10.1371/journal.pone.0109095 · 3.23 Impact Factor
  • Source
    • "Experimental evidence abounds on the ability of Myd88 to influence immune and inflammatory signaling through multiple pathways, and protective immunity against many pathogens [26,28,34,35,36,37,38,39]. In view of reports suggesting the important roles played by Myd88 signaling in the generation of humoral immune responses, we explored the potential utility of Myd88 as a genetic adjuvant in plasmid vaccination against rabies. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose Myeloid differentiation factor 88 (Myd88), a ubiquitous Toll-like receptor adaptor molecule, has been reported to play important roles in B cell responses to infections and vaccination. The present study evaluated the effects of genetic adjuvanting with Myd88 on the immune responses to a plasmid DNA rabies vaccine. Materials and Methods Plasmids encoding rabies glycoprotein alone (pIRES-Rgp) or a fragment of Myd88 gene in addition (pIRES-Rgp-Myd) were constructed and administered intramuscularly or intrademally in Swiss albino mice (on days 0, 7, and 21). Rabies virus neutralizing antibody (RVNA) titres were estimated in the mice sera on days 14 and 28 by rapid fluorescent focus inhibition test. The protective efficacy of the constructs was evaluated by an intracerebral challenge with challenge virus standard virus on day 35. Results Co-expression of Myd88 increased RVNA responses to pIRES-Rgp by 3- and 2-folds, following intramuscular and intradermal immunization, respectively. pIRES-Rgp protected 80% of the mice following intramuscular and intradermal immunizations, while pIRES-Rgp-Myd afforded 100% protection following similar administrations. Conclusion Genetic adjuvanting with Myd88 enhanced the RVNA responses and protective efficacy of a plasmid DNA rabies vaccine. This strategy might be useful for rabies vaccination of canines in the field, and needs further evaluation.
    07/2014; 3(2):202-11. DOI:10.7774/cevr.2014.3.2.202
  • Source
    • "Upon stimulation with IL-6, 12-O-tetradecanoylphorbol-13-acetate (TPA) or lipopolysaccharide (LPS), B cells are activated, rapidly proliferate and initiate differentiation processes leading to increased antibody secretion, e.g., immunoglobulin M (IgM) [19,21,22,25,26]. To determine which stimulator was most efficient for the present study, we treated SKW 6.4 cells with rhIL-6 (50-1600 U/ml), TPA (1-1000 nM) or LPS (1-5 μM) for 4 days. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Cannabinoid receptor 2 (CB2) is expressed predominantly in the immune system, particularly in plasma cells, raising the possibility that targeting the CB2 pathway could yield an immunomodulatory effect. Although the role of CB2 in mediating immunoglobulin class switching has been reported, the effects of targeting the CB2 pathway on immunoglobulin secretion per se remain unclear. Methods Human B cell line SKW 6.4, which is capable of differentiating into IgM-secreting cells once treated with human IL-6, was employed as the cell model. SKW 6.4 cells were incubated for 4 days with CB2 ligands plus IL-6 (100 U/ml). The amount of secreted IgM was determined by an ELISA. Cell proliferation was determined by the 3H-Thymidine incorporation assay. Signal molecules involved in the modulation of IgM secretion were examined by real-time RT-PCR and Western blot analyses or by using their specific inhibitors. Results We demonstrated that CB2 inverse agonists SR144528 and AM630, but not CB2 agonist HU308 or CB1 antagonist SR141716, effectively inhibited IL-6-induced secretion of soluble IgM without affecting cell proliferation as measured by thymidine uptake. SR144528 alone had no effects on the basal levels of IgM in the resting cells. These effects were receptor mediated, as pretreatment with CB2 agonist abrogated SR144528-mediated inhibition of IL-6 stimulated IgM secretion. Transcription factors relevant to B cell differentiation, Bcl-6 and PAX5, as well as the protein kinase STAT3 pathway were involved in the inhibition of IL-6-induced IgM by SR144528. Conclusions These results uncover a novel function of CB2 antagonists and suggest that CB2 ligands may be potential modulators of immunoglobulin secretion.
    BMC pharmacology & toxicology 06/2014; 15(1):30. DOI:10.1186/2050-6511-15-30
Show more

Preview (2 Sources)

3 Reads
Available from