A Toll-Like Receptor 2 Ligand Stimulates Th2 Responses In Vivo, via Induction of Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and c-Fos in Dendritic Cells

Dillon, Stephanie M.; Agrawal, Anshu; Dyke, Thomas E. Van; Landreth, Gary E.; McCauley, Laurie K.; Koh, Amy J.; Maliszewski, Charles R.; Akira, Shizuo; Pulendran, Bali

doi:10.4049/jimmunol.172.8.4733

Cited by 415 publications

(462 citation statements)

References 78 publications

Supporting

Mentioning

394

Contrasting

Unclassified

Order By: Relevance

“…The differences in results, therefore, likely reflect cellular differences in the usage of cFos/AP-1 and/or differences in the stimulation of cFos/AP-1 (single vs. dual stimulation). Consistent with this hypothesis, cFos appears to have no negative effects on IL-6 production by TLR-stimulated DC from cFos -/-mice [44]. Our data indicate that the role of cFos in B cell cytokine production may be more complex than previously thought, and worthy of further investigation.…”

Section: Discussionsupporting

confidence: 84%

TLR7 and CD40 cooperate in IL‐6 production via enhanced JNK and AP‐1 activation

Bush

Bishop

2008

Eur J Immunol

View full text Add to dashboard Cite

During vaccination or infection, adaptive and innate immune receptors of B cells are engaged by microbial antigens/ligands. A better understanding of how innate and adaptive signaling pathways interact could enlighten B lymphocyte biology as well as aid immunotherapy strategies and vaccine design. To address this goal, we examined the effects of TLR stimulation on BCR and CD40-induced B cell activation. Synergistic production of IL-6 was observed in both human and mouse primary B cells stimulated through B cell antigen receptors, CD40 and TLR7, and these two receptors also cooperated independently of BCR signals. The enhanced IL-6 production was dependent upon the activity of c-Jun kinase (JNK) and cFos. Dual stimulation through CD40 and TLR7 markedly enhanced JNK activity. The increased level of active JNK in dual-stimulated cells was accompanied by an increase in the level of active AP-1 monomers cJun and cFos. The stimulation of B cells through both CD40 and TLR7 therefore enhanced the production of cytokines through increased JNK signaling and AP-1 activity. In addition, the dual stimulation increased cFos/AP-1 species in stimulated cells, effectively expanding the repertoire of AP-1 dimers as compared to singly stimulated B cells. IntroductionNatural immune responses to microbes and responses induced by vaccination involve the cooperation of innate and adaptive immunity. B lymphocytes express receptors that allow them to respond to both antigen-specific and innate immune stimuli [1,2]. One of the key receptors involved in adaptive humoral responses is the TNF receptor superfamily member CD40. The interaction of CD40 on B cells with its ligand CD154, expressed by activated T cells, is integral to immunoglobulin production, isotype switching, and the formation of germinal centers [3], important events in the development of long-lived humoral memory. CD40 stimulation also contributes to B cell antigen presentation by the upregulation of T cell co-stimulatory molecules and production of acute phase cytokines such as . Previous studies have shown that dual stimulation of B cells through the BCR and CD40 leads to an enhancement of Ig and cytokine production [7]. However, the effects and mechanisms of interactions between innate immune receptors and BCR or CD40 expressed by B cells are not yet well defined.B cells can be activated through engagement of a variety of innate immune receptors, including Toll-like receptors (TLR). TLR are related to the Drosophila receptor Toll, important for dorsal-ventral patterning in the developing fly as well as resistance to microbes [8]. The TLR in higher organisms act as sensors of infection or 'danger' by recognizing molecular patterns associated with microbes and/or cellular damage. As natural surveyors of environmental stresses, TLR induce immune cell activity and direct the initial stages of immune responses [9]. Of the 13 TLR mammalian genes [11,12]. TLR7 and -8 bind singlestranded RNA as natural ligands, but also confer responsiveness to guanosine derivatives and the imi...

show abstract

Section: Discussionsupporting

confidence: 84%

TLR7 and CD40 cooperate in IL‐6 production via enhanced JNK and AP‐1 activation

Bush

Bishop

2008

Eur J Immunol

View full text Add to dashboard Cite

show abstract

“…inhibit early IL-4 production by responding CD4 T cells and thus inhibit Th2 cell development. Our data indicating that TLR 2 ligands profoundly inhibit Th2 cell development are contradictory to those findings that have suggested the role of TLR2 ligands in the induction of Th2 responses (20,(33)(34)(35)(36)(37)(38). Nevertheless, there is a large body of published data that is consistent with our findings showing that TLR2 ligands, including Pam 3 Cys, either promote Th1 responses or inhibit Th2 responses (39 -47).…”

Section: Discussioncontrasting

confidence: 68%

“…This is intriguing because there are reports that S- (2,3- 4 -OH,trihydrochloride (Pam 3 Cys), another TLR2 ligand, favors Th2 cell differentiation perhaps by enhancing production of IL-10 by DCs (20). To examine this issue, we stimulated DCs with Pam 3 Cys and cocultured them with OT-II Th cells in the presence or absence of a blocking anti-IL10R Ab.…”

Section: Tlr Agonists Not Cytokines Activate Dcs To Suppress Early mentioning

confidence: 99%

Suppression of Early IL-4 Production Underlies the Failure of CD4 T Cells Activated by TLR-Stimulated Dendritic Cells to Differentiate into Th2 Cells

Sun

Pearce

2007

The Journal of Immunology

View full text Add to dashboard Cite

Dendritic cells (DCs) activated through TLRs provide a potent negative signal for Th2 cell development that is independent of positive signals for Th1 cell development such as IL-12 and IFN-γ. In this study we demonstrate that the ability of TLR-activated DCs to suppress Th2 cell development is Ag dose-independent and unique to DCs that have been activated through TLRs vs by cytokines. We show that TLR-activated DCs inhibit early IL-4 production by CD4 T cells and thus inhibit their ability to subsequently increase GATA-3 expression and commit to the Th2 lineage. This occurs independently of expression of the GATA-3 antagonist T-bet. Although CD4 T cells activated by TLR-activated DCs make IL-2, they are not capable of phosphorylating STAT5 in response to this cytokine. This inhibition of responsiveness to IL-2 appears to underlie the failure to make early IL-4. Our findings suggest that DCs provide instructional signals for T cell differentiation before cytokine-mediated Th cell selection and outgrowth.

show abstract

“…There is a growing body of evidence suggesting that bacterial components with immune adjuvant activity, including CpG DNA [13], Nme PorB [31] or Shigella porins [20], act via Toll-like receptors (TLRs) and can induce both a Th1-and a Th2-immune response [45,[68][69][70]. In addition, it has been recently shown that TLR2 mediates Th1 responses via direct stimulation of Th1 cells and via IL-12 production by APCs, and that TLR2-mediated INF-γ production is crucial for protective immunity against several infectious pathogens [71].…”

Section: Discussionmentioning

confidence: 99%

The PorB porin from commensal Neisseria lactamica induces Th1 and Th2 immune responses to ovalbumin in mice and is a potential immune adjuvant

Liu

Wetzler

Massi

2008

Vaccine

View full text Add to dashboard Cite

Porins from pathogenic Neisseriae are among several bacterial products with immune adjuvant activity. N. meningitidis (Nme) PorB, has been shown to induce immune cells activation in a TLR2-dependent manner and acts as a vaccine immune adjuvant. The PorB porin from Neisseria lactamica (Nlac), a common nasopharyngeal commensal shares significant structural and functional similarities with Nme PorB. In this work we ask whether the immune adjuvant ability of porins from pathogenic Neisserial strains is a characteristic shared with porins from non-pathogenic Neisserial species or whether it is unique for bacterial products derived from microorganisms capable of inducing inflammation and disease. We evaluate the potential immune adjuvant effect of Nlac PorB in mice using ovalbumin (OVA) as a prototype antigen. Immunization with Nlac PorB/OVA induced high OVA-specific IgG and IgM titers compared to OVA alone, similar to other adjuvants such as Nme PorB and alum. High titers of IgG1 and IgG2b were detected as well as production of IL-4, IL-10, IL-12 and INF-γ in response to Nlac PorB, consistent with induction of both a Th1-type and a Th2-type immune response. OVA-specific proliferation was also determined in splenocytes from Nlac PorB/OVA immunized mice. In addition, B cell activation in vitro and cytokine production in response to Nlac PorB was found to be mediated by TLR2, in a similar manner to Nme PorB.

show abstract

A Toll-Like Receptor 2 Ligand Stimulates Th2 Responses In Vivo, via Induction of Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and c-Fos in Dendritic Cells

Cited by 415 publications

References 78 publications

TLR7 and CD40 cooperate in IL‐6 production via enhanced JNK and AP‐1 activation

TLR7 and CD40 cooperate in IL‐6 production via enhanced JNK and AP‐1 activation

Suppression of Early IL-4 Production Underlies the Failure of CD4 T Cells Activated by TLR-Stimulated Dendritic Cells to Differentiate into Th2 Cells

The PorB porin from commensal Neisseria lactamica induces Th1 and Th2 immune responses to ovalbumin in mice and is a potential immune adjuvant

Contact Info

Product

Resources

About