TLR4 Ligands Augment Antigen-Specific CD8
            <sup>+</sup>
            T Lymphocyte Responses Elicited by a Viral Vaccine Vector

Rhee, Elizabeth G.; Kelley, Rosemary; Agarwal, Isha; Lynch, Diana M.; Porte, Annalena La; Simmons, Nathaniel L.; Clark, Sarah L.; Barouch, Dan H.

doi:10.1128/jvi.00928-10

Cited by 32 publications

(33 citation statements)

References 42 publications

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“…The activation of TLRs by their cognate ligands leads to inflammatory cytokine production and up-regulation of costimulatory signals and MHC molecules, thereby linking innate recognition with adaptive T and B cell immune responses, as well as memory responses after immune system encounters any pathogen (32,33). Thus, the emerging concept of utilizing TLR agonists as vaccine adjuvant and strategizing to manipulate TLR signaling in this regard are considered herein.…”

Section: Discussionmentioning

confidence: 99%

Toll-like Receptor 4 (TLR4) Is Essential for Hsp70-like Protein 1 (HSP70L1) to Activate Dendritic Cells and Induce Th1 Response

Fang¹,

Wu²,

Huang

et al. 2011

Journal of Biological Chemistry

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Toll-like receptors (TLRs) play important roles in initiation of innate and adaptive immune responses. Emerging evidence suggests that TLR agonists can serve as potential adjuvant for vaccination. Heat shock proteins (HSPs), functionally serving as TLR4 agonists, have been proposed to act as Th1 adjuvant. We have identified a novel Hsp70 family member, termed Hsp70-like protein 1 (Hsp70L1), shown that Hsp70L1 is a potent T helper cell (Th1) polarizing adjuvant that contributes to antitumor immune responses. However, the underlying mechanism for how Hsp70L1 exerts its Th1 adjuvant activity remains to be elucidated. In this study, we found that Hsp70L1 binds directly to TLR4 on

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Section: Discussionmentioning

confidence: 99%

Toll-like Receptor 4 (TLR4) Is Essential for Hsp70-like Protein 1 (HSP70L1) to Activate Dendritic Cells and Induce Th1 Response

Fang¹,

Wu²,

Huang

et al. 2011

Journal of Biological Chemistry

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“…Recently, there has been considerable interest in designing adjuvants for human vaccines that target the TRIF pathway of signaling downstream of TLR4 (10)(11)(12)(13). It is clear that the TRIF signaling pathway can induce DC maturation that is sufficient for induction of adaptive immunity without the overwhelming inflammatory response induced by the MyD88 signaling pathway (14).…”

Section: Map Kinases | Lps | Poly I:c | Mavs | Nf-κb Activationmentioning

confidence: 99%

Differential outcome of TRIF-mediated signaling in TLR4 and TLR3 induced DC maturation

Jain

Gao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Recognition of pathogen-associated molecular patterns by Tolllike receptors (TLRs) on dendritic cells (DCs) leads to DC maturation, a process involving up-regulation of MHC and costimulatory molecules and secretion of proinflammatory cytokines. All TLRs except TLR3 achieve these outcomes by using the signaling adaptor myeloid differentiation factor 88. TLR4 and TLR3 can both use the Toll-IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF)-dependent signaling pathway leading to IFN regulatory factor 3 (IRF3) activation and induction of IFN-β and -α4. The TRIF signaling pathway, downstream of both of these TLRs, also leads to DC maturation, and it has been proposed that the type I IFNs act in cis to induce DC maturation and subsequent effects on adaptive immunity. The present study was designed to understand the molecular mechanisms of TRIF-mediated DC maturation. We have discovered that TLR4-TRIF-induced DC maturation was independent of both IRF3 and type I IFNs. In contrast, TLR3-mediated DC maturation was completely dependent on type I IFN feedback. We found that differential activation of mitogen-activated protein kinases by the TLR4-and TLR3-TRIF axes determined the type I IFN dependency for DC maturation. In addition, we found that the adjuvanticity of LPS to induce T-cell activation is completely independent of type I IFNs. The important distinction between the TRIF-mediated signaling pathways of TLR4 and TLR3 discovered here could have a major impact in the design of future adjuvants that target this pathway.

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“…61 In conclusion, we demonstrated that HS has potent effects as vaccine adjuvant when co-immunized with inactivated vaccines in mice. To further explore the underlying mechanism of HS adjuvanticity, the transcriptional expression patterns of DCs exposed to HS was assessed.…”

Section: Discussionmentioning

confidence: 60%

Gene expression profiles identify both MyD88-independent and MyD88-dependent pathways involved in the maturation of dendritic cells mediated by heparan sulfate: A novel adjuvant

Wang

Shi³

et al. 2014

Human Vaccines & Immunotherapeutics

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The traditional vaccine adjuvant research is mainly based on the trial and error method, and the mechanisms underlying the immune system stimulation remaining largely unknown. We previously demonstrated that heparan sulfate (HS), a TLR-4 ligand and endogenous danger signal, effectively enhanced humoral and cellular immune responses in mice immunized by HBsAg. This study aimed to evaluate whether HS induces better humoral immune responses against inactivated Hepatitis A or Rabies Vaccines, respectively, compared with traditional adjuvants (e.g. Alum and complete Freund's adjuvant). In order to investigate the molecular mechanisms of its adjuvanticity, the gene expression pattern of peripheral blood monocytes derived DCs (dendritic cells) stimulated with HS was analyzed at different times points. Total RNA was hybridized to Agilent SurePrint G3 Human Gene Expression 8 £ 60 K one-color oligo-microarray. Through intersection analysis of the microarray results, we found that the Toll-like receptor signaling pathway was significantly activated, and NF-kB, TRAF3 and IRF7 were activated as early as 12 h, and MyD88 was activated at 48 h post-stimulation. Furthermore, the expression of the surface marker CD83 and the co-stimulatory molecules CD80 and CD86 was up-regulated as early as 24 h. Therefore, we speculated that HS-induced human monocyte-derived DC maturation may occur through both MyD88-independent and dependent pathways, but primarily through the former (TRIF pathway). These data provide an important basis for understanding the mechanisms underlying HS enhancement of the immune response.

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TLR4 Ligands Augment Antigen-Specific CD8 ⁺ T Lymphocyte Responses Elicited by a Viral Vaccine Vector

Cited by 32 publications

References 42 publications

Toll-like Receptor 4 (TLR4) Is Essential for Hsp70-like Protein 1 (HSP70L1) to Activate Dendritic Cells and Induce Th1 Response

Toll-like Receptor 4 (TLR4) Is Essential for Hsp70-like Protein 1 (HSP70L1) to Activate Dendritic Cells and Induce Th1 Response

Differential outcome of TRIF-mediated signaling in TLR4 and TLR3 induced DC maturation

Gene expression profiles identify both MyD88-independent and MyD88-dependent pathways involved in the maturation of dendritic cells mediated by heparan sulfate: A novel adjuvant

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TLR4 Ligands Augment Antigen-Specific CD8 + T Lymphocyte Responses Elicited by a Viral Vaccine Vector

Cited by 32 publications

References 42 publications

Toll-like Receptor 4 (TLR4) Is Essential for Hsp70-like Protein 1 (HSP70L1) to Activate Dendritic Cells and Induce Th1 Response

Toll-like Receptor 4 (TLR4) Is Essential for Hsp70-like Protein 1 (HSP70L1) to Activate Dendritic Cells and Induce Th1 Response

Differential outcome of TRIF-mediated signaling in TLR4 and TLR3 induced DC maturation

Gene expression profiles identify both MyD88-independent and MyD88-dependent pathways involved in the maturation of dendritic cells mediated by heparan sulfate: A novel adjuvant

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TLR4 Ligands Augment Antigen-Specific CD8 ⁺ T Lymphocyte Responses Elicited by a Viral Vaccine Vector