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: 5.36). 07/2007; 178(12):7779-86. DOI: 10.4049/jimmunol.178.12.7779
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Endosomal TLRs play an important role in systemic autoimmune diseases, such as systemic erythematosus lupus, in which DNA- and RNA-associated autoantigens activate autoreactive B cells through TLR9- and TLR7-dependent pathways. Nevertheless, TLR9-deficient autoimmune-prone mice develop more severe clinical disease, whereas TLR7-deficient and TLR7/9-double deficient autoimmune-prone mice develop less severe disease. To determine whether the regulatory activity of TLR9 is B cell intrinsic, we directly compared the functional properties of autoantigen-activated wild-type, TLR9-deficient, and TLR7-deficient B cells in an experimental system in which proliferation depends on BCR/TLR coengagement. In vitro, TLR9-deficient cells are less dependent on survival factors for a sustained proliferative response than are either wild-type or TLR7-deficient cells. The TLR9-deficient cells also preferentially differentiate toward the plasma cell lineage, as indicated by expression of CD138, sustained expression of IRF4, and other molecular markers of plasma cells. In vivo, autoantigen-activated TLR9-deficient cells give rise to greater numbers of autoantibody-producing cells. Our results identify distinct roles for TLR7 and TLR9 in the differentiation of autoreactive B cells that explain the capacity of TLR9 to limit, as well as TLR7 to promote, the clinical features of systemic erythematosus lupus. Copyright © 2015 by The American Association of Immunologists, Inc.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: RhoF is a member of the Rho GTPase family that has been implicated in various cell functions including long filopodia formation, adhesion, and migration of cells. Although RhoF is expressed in lymphoid tissues, the roles of RhoF in B cell development remain largely unclear. On the other hand, other members of the Rho GTPase family, such as Cdc42, RhoA, and Rac, have been intensively studied and are known to be required for B cell development in the bone marrow and spleen. We hypothesized that RhoF is also involved in B cell development. To examine our hypothesis, we analyzed B cell development in RhoF knockout (KO) mice and found a significant reduction in marginal zone (MZ) B cells in the spleen, although T cell development in the thymus and spleen was not affected. Consistent with these results, the width of the MZ B cell region in the spleen was significantly reduced in the RhoF KO mice. However, the antigen-specific antibody titer of IgM and IgG3 after MZ B cell-specific antigen (T cell-independent antigen, type I) stimulation was not affected by RhoF deletion. Furthermore, we demonstrated that RhoF was dispensable for stromal cell-derived factor-1α- and B lymphocyte chemoattractant-induced B cell migration. These results suggest that RhoF promotes MZ B cell development in the spleen.
    Nagoya journal of medical science 08/2014; 76(3-4):293-305. · 0.80 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To date, the response of B cells to specific pathogens has been only scarcely addressed in teleost. In the current work, we have demonstrated that viral hemorrhagic septicemia virus (VHSV), a fish rhabdovirus, has the capacity to infect rainbow trout spleen IgM(+) cells although the infection is not productive. Consequently, we have studied the effects of VHSV on IgM(+) cell functionality comparing these effects to those elicited by a TLR3 ligand, Poly I:C. We found that Poly I:C and VHSV significantly up-regulated TLR3 and type I interferon (IFN) transcription in spleen and blood IgM(+) cells. Further effects included the up-regulated transcription of the CK5B chemokine. Significant inhibition of some of these effects in presence of bafilomicyn A1 (BAF), an inhibitor of endosomal acidification, suggests the involvement of an intracellular TLR in these responses. In the case of VHSV, these transcriptional effects were dependent on viral entry into B cells and initiation of viral transcription. VHSV also provoked the activation of NF-κΒ and the up-regulation of MHC-II cell surface expression on IgM(+) cells, that along with an increased transcription of the co-stimulatory molecules CD80/86 and CD83 pointed to a VHSV-induced IgM(+) cell activation towards an antigen-presenting profile. Finally, despite the moderate effects of VHSV on IgM(+) cell proliferation, a consistent effect on IgM(+) cell survival was detected. Innate immune responses to pathogens established through their recognition by PRRs have been traditionally ascribed to innate cells. However, recent evidence in mammals has revealed that innate pathogen recognition by B lymphocytes is a crucial factor in shaping the type of immune response that is mounted. In teleost, these immediate effects of viral encounter on B lymphocytes have not been addressed to date. In our study, we have demonstrated that VHSV infection provoked immediate transcriptional effects in B cells, at least partially mediated by intracellular PRR signaling. VHSV also activated NF-κΒ and increased IgM(+) cell survival. Interestingly, VHSV activated B lymphocytes towards an antigen-presenting profile, suggesting an important role of IgM(+) cells in VHSV presentation. Our results provide a first description of the effects provoked by fish rhabdoviruses through their early interaction with teleost B cells. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
    Journal of Virology 11/2014; DOI:10.1128/JVI.03080-14 · 4.65 Impact Factor


Available from