Role of TLR in B Cell Development: Signaling through TLR4 Promotes B Cell Maturation and Is Inhibited by TLR2

Hayashi, Elize A.; Akira, Shizuo; Nóbrega, Alberto

doi:10.4049/jimmunol.174.11.6639

Cited by 79 publications

(70 citation statements)

References 45 publications

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“…Another feature of B lymphocytes derived from B6 lpr/lpr -TLR4-deficient mice is the lack of CD23. In this regard, in vitro experiments have demonstrated that CD23 expression can be induced on B cells by TLR4 engagement during late steps of B lymphocyte maturation (33). The low level of CD23, observed on cells from our B6…”

Section: Discussionmentioning

confidence: 82%

“…Flow cytometry analysis of B cell lineage in bone marrow from TLR2-and TLR4-deficient mice (33), but also from B6 lpr/lpr , B6 lpr/lpr -TLR2 Ϫ/Ϫ , and B6 lpr/lpr -TLR4 Ϫ/Ϫ showed no significant abnormality in the pre-B, immature B, or mature B cell populations (data not shown). To explain the decrease of autoantibody production directed against T-independent Ags, including DNA, cardiolipin, and RF in TLR-deficient mice, we analyzed splenic B cell subsets in B6 lpr/lpr mice (5.4 Ϯ 1.6) ( Fig.…”

Section: B Cell Subsets In Tlr2-and Tlr4-deficient B6 Lpr/lpr Micementioning

confidence: 99%

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Critical Role of TLR2 and TLR4 in Autoantibody Production and Glomerulonephritis in lpr Mutation-Induced Mouse Lupus

Lartigue

Colliou²,

Calbo³

et al. 2009

The Journal of Immunology

133

100

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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathogenic autoantibodies directed against nuclear Ags and immune complex deposits in damaged organs. Environmental factors have been thought to play a role in the onset of the disease. The recognition of these factors is mediated by TLRs, in particular TLR2 and TLR4 which bind pathogen-associated molecular patterns of Gram+ and Gram− bacteria, respectively. We attempted to determine the role of these TLRs in SLE by creating TLR2- or TLR4-deficient C57BL/6lpr/lpr mice. These mice developed a less severe disease and fewer immunological alterations. Indeed, in C57BL/6lpr/lpr-TLR2 or -TLR4-deficient mice, glomerular IgG deposits and mesangial cell proliferation were dramatically decreased and antinuclear, anti-dsDNA, and anti-cardiolipin autoantibody titers were significantly reduced. However, the response against nucleosome remained unaffected, indicating a role of TLR2 and TLR4 in the production of Abs directed against only certain categories of SLE-related autoantigens. Analysis of B cell phenotype showed a significant reduction of marginal zone B cells, particularly in C57BL/6lpr/lpr-TLR4-deficient mice, suggesting an important role of TLR4 in the sustained activation of these cells likely involved in autoantibody production. Interestingly, the lack of TLR4 also affected the production of cytokines involved in the development of lupus disease.

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Section: Discussionmentioning

confidence: 82%

Section: B Cell Subsets In Tlr2-and Tlr4-deficient B6 Lpr/lpr Micementioning

confidence: 99%

Critical Role of TLR2 and TLR4 in Autoantibody Production and Glomerulonephritis in lpr Mutation-Induced Mouse Lupus

Lartigue

Colliou²,

Calbo³

et al. 2009

The Journal of Immunology

133

100

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“…Our group has previously shown that TLR4 agonists promote the generation of CD23 + B cells with a transitional T2-like phenotype in a system of B cell differentiation in vitro from purified B cell precursors (25), suggesting a role for TLR4 signal in B cell maturation. We have obtained convincing evidence that such effect is due to differentiation of CD93 + CD23 2 immature B cells into CD93 + CD23 + T2-like B cells and does not involve B cell proliferation.…”

Section: Generation Of Cd23 + B Cells In Vitro In the Presence Of Lpsmentioning

confidence: 99%

“…+ transitional B cells with a "T2-like" phenotype from BM B cell precursors in vitro (25) suggest an alternative mode of action of LPS on immature B cells, distinct from classical B cell activation and more compatible with the progression in maturation of the developing B lymphocyte.…”

mentioning

confidence: 99%

TLR4 Promotes B Cell Maturation: Independence and Cooperation with B Lymphocyte-Activating Factor

Hayashi

Granato

Paiva

et al. 2010

The Journal of Immunology

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We have previously shown that TLR4 triggering promotes the generation of CD23+CD93+ transitional T2-like cells in vitro from mouse B cell precursors, suggesting a possible role for this receptor in B cell maturation. In this study, we perform an extensive study of cell surface markers and functional properties of B cells matured in vitro with LPS, comparatively with the well-known B cell maturation factor B lymphocyte-activating factor (BAFF). LPS increased generation of CD23+ transitional B cells in a TLR4-dependent way, upregulating IgD and CD21 and downregulating CD93, without inducing cell proliferation, in a manner essentially equivalent to BAFF. For both BAFF and LPS, functional maturation of the IgM+CD23+CD93+ cells was confirmed by their higher proliferative response to anti-CD40 plus IL-4 compared with IgM+CD23negCD93+ cells. BAFF-R-Fc–mediated neutralization experiments showed that TLR4-induced B cell maturation was independent of BAFF. Distinct from BAFF, maturation by LPS relied on the activation of canonical NF-κB pathway, and the two factors together had complementary effects, leading to higher numbers of IgM+CD23+CD93+ cells with their simultaneous addition. Importantly, BCR cross-linking abrogated the generation of CD23+ B cells by LPS or BAFF, indicating that signals mimicking central tolerance act on both systems. Addition of cyclosporin A reverted BCR-mediated inhibition, both for BAFF and LPS, suggesting similar regulation of signaling pathways by calcineurin. Finally, LPS-injected mice showed a rapid increase of mature B cells in the bone marrow, suggesting that TLR4 signaling may effectively stimulate B cell maturation in vivo, acting as an accessory stimulus in B cell development, complementary to the BAFF physiological pathway.

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“…They might participate in the regulation of B-cell differentiation process. 9 Toll-like receptor stimulation is required as a third signal for the activation of human naive B cells. 10 In human naive B cells, TLRs are expressed at low levels, but the expression of some TLRs is induced upon Bcell receptor (BCR) triggering.…”

mentioning

confidence: 99%

Toll‐like receptors on B‐CLL cells: expression and functional consequences of their stimulation

Rozkova

Novotná

Pytlík

et al. 2009

Intl Journal of Cancer

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Toll‐like receptor (TLR) stimulation plays a crucial role in the homeostasis of human B cells. We investigated the expression of TLRs 1–9 on the cells of B‐cell chronic lymphocytic leukemia (B‐CLL) and analyzed the functional consequences of TLR stimulation on leukemic cells. We showed that B‐CLL cells express similar set of TLRs as memory B cells of healthy donors, i.e. TLR‐1, TLR‐2, TLR‐6, TLR‐7 and TLR‐9. However, in contrast to memory B cells, B‐CLL cells lack TLR‐4 expression. Expression of TLRs correlates with their capacity to respond to specific TLR agonists. At the level of phenotype, ODN2006 (TLR‐9 agonist) is the most potent stimulus. B‐CLL cells also respond to the stimulation with loxoribine, Pam3CSK4 and MALP‐2 (TLR‐7, TLR1/TLR2 and TLR2/TLR6 agonists, respectively). TLR‐7 and TLR‐9 stimulation induces production of IL‐6 and TNFα. In 47% of tested patients, treatment with ODN2006, MALP‐2 and Pam3CSK4 reduced leukemic cells survival. Stimulation of B‐CLL cells with TLR‐9 agonists, loxoribine, MALP‐2 and Pam3CSK4 induces significant proliferation. We report that TLR stimulation induces expression of CD38, a negative prognostic marker, on B‐CLL cells. Expression of CD38 is induced by direct stimulation of B‐CLL cells through TLR‐7 and TLR‐9 or CD38 can be induced on B‐CLL cells indirectly by a soluble factor induced in non‐B‐CLL cells after stimulation with TLR‐2, TLR‐3 or TLR‐5 agonists; the nature of this factor remains unknown. Our results argue for cautious evaluation of immunointervention strategies based on the administration of TLR agonists in the treatment of B‐CLL as their effects on B‐CLL cells may be tumor promoting as well as tumor suppressing.

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Role of TLR in B Cell Development: Signaling through TLR4 Promotes B Cell Maturation and Is Inhibited by TLR2

Cited by 79 publications

References 45 publications

Critical Role of TLR2 and TLR4 in Autoantibody Production and Glomerulonephritis in lpr Mutation-Induced Mouse Lupus

Critical Role of TLR2 and TLR4 in Autoantibody Production and Glomerulonephritis in lpr Mutation-Induced Mouse Lupus

TLR4 Promotes B Cell Maturation: Independence and Cooperation with B Lymphocyte-Activating Factor

Toll‐like receptors on B‐CLL cells: expression and functional consequences of their stimulation

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