Toll-like receptor ligands synergize through distinct dendritic cell pathways to induce T cell responses: Implications for vaccines

Zhu, Qing; Egelston, Colt; Aravindhan, Vivekanandhan; Uematsu, Satoshi; Akira, Shizuo; Klinman, Dennis M.; Belyakov, Igor M.; Berzofsky, Jay A.

doi:10.1073/pnas.0805325105

Cited by 163 publications

(160 citation statements)

References 49 publications

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“…Certain molecular adjuvants, such as Toll-like receptor (TLR) agonists and cytokines, can improve the quantity and quality of antigen-specific T-cell responses (6,7). Studies in mice showed that TLR2, -3, and -9 agonists activate and mature dendritic cells (DCs) to enhance immune responses (8,9) and our laboratory discovered a synergistic adjuvant effect of a combination of these agonists (9,10). We and others have also found that IL-15 is a strong cytokine adjuvant, as it promotes the homeostatic expansion of CD8 + memory T cells, and the induction of higher avidity, longer-lived T cells (11)(12)(13)(14).…”

mentioning

confidence: 99%

Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques

Sui

Zhu

Gagnon

et al. 2010

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

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110

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Adjuvant effects on innate as well as adaptive immunity may be critical for inducing protection against mucosal HIV and simian immunodeficiency virus (SIV) exposure. We therefore studied effects of Toll-like receptor agonists and IL-15 as mucosal adjuvants on both innate and adaptive immunity in a peptide/poxvirus HIV/SIV mucosal vaccine in macaques, and made three critical observations regarding both innate and adaptive correlates of protection: (i) adjuvant-alone without vaccine antigen impacted the intrarectal SIVmac251 challenge outcome, correlating with surprisingly long-lived APOBEC3G (A3G)-mediated innate immunity; in addition, even among animals receiving vaccine with adjuvants, viral load correlated inversely with A3G levels; (ii) a surprising threshold-like effect existed for vaccine-induced adaptive immunity control of viral load, and only antigen-specific polyfunctional CD8 + T cells correlated with protection, not tetramer + T cells, demonstrating the importance of T-cell quality; (iii) synergy was observed between Toll-like receptor agonists and IL-15 for driving adaptive responses through the up-regulation of IL-15Rα, which can present IL-15 in trans, as well as for driving the innate A3G response. Thus, strategic use of molecular adjuvants can provide better mucosal protection through induction of both innate and adaptive immunity.

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mentioning

confidence: 99%

Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques

Sui

Zhu

Gagnon

et al. 2010

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

Self Cite

110

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“…The up-regulation of the MyD88 gene expression correlated with the increased expression of CD11c and CD86 genes in splenic MNCs isolated from mice treated with sole Cpg ODN or tumor vaccine suggesting again that the maturation of APCs (including the DCs) was triggered after the injection of tumor vaccine (37). unlike in the splenic MNCs, a significant up-regulation of CD11c and CD86 in MNCs isolated from the bone marrow of treated mice was not detected earlier than 3 days after the first application of the vaccine or the vaccine components.…”

Section: Discussionmentioning

confidence: 95%

Tumor vaccine composed of CpG ODN class C and irradiated tumor cells up-regulates the expression of genes characteristic of mature dendritic cells and of memory cells

Novaković

2011

Int J Oncol

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Abstract. Only properly mature dendritic cells (DCs) in the presence of tumor antigens accomplish to activate all of the elements of the immune network and have the potential to induce tumor-specific effectors and memory T cells. In the current study, we firstly aimed to investigate the in vivo maturation of antigen presenting cells (APCs) at the molecular level by following the expression of CD11c, CD86 and MyD88 genes in the mixture of mononuclear cells after treatment of mice with a tumor vaccine composed of C-class CpG oligodeoxynucletides (CpG ODN) and irradiated melanoma B16F1 tumor cells. The second objective was to define whether the tumor vaccine induces generation of memory T cells (CD44 hi CD62L lo/hi CD27 hi ). Finally, based on gene expression pattern we aimed to determine the tissue distribution and homing of the (mature) APCs and memory cells after vaccination. We demonstrated that by tumor vaccine the APCs (including DCs) are manipulated in vivo. By this kind of vaccine, the differentiation and maturation of APCs is triggered primarily in the spleen and is subsequently followed by the migration of these APCs to the bone marrow. Once in the bone marrow, these APCs play a crucial role in the development and maintenance of long-lived memory T cells capable of preventing a relapse of malignant disease. In conclusion, our results provide insight into the nature and scope of the antitumor immune response elicited by this kind of tumor vaccine in vivo. We showed that the maturation of APCs is a prerequisite for the generation of effective longterm antitumor immunity.

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“…Four TLRs (TLR2-5) are expressed in both normal ovary epithelial cells and ovarian cancer cell lines (Zhou et al, 2009). The significance of the expression of multiple TLRs in a wide range of cancer cells is not fully understood; however, simultaneous activation of multiple TLR types might be able to enhance the biological response, as in the case of synergistic effects by combined TLR ligation reported for cytokine production in DCs (Whitmore et al, 2004;Roelofs et al, 2005;Warger et al, 2006;Gautier et al, 2005;Theiner et al, 2007;Zhu et al, 2008;Krummen et al, 2010) and macrophages (Sato et al, 2000;Ouyang et al, 2007). It is possible that tumor cells express multiple TLRs to recognize various DAMPs in their microenvironment, and thereby enhance the biological process triggered by TLR activation to produce favorable conditions for growth and survival.…”

Section: Positive Effects Of Tlrs In Cancer Developmentmentioning

confidence: 99%

Innate Immunity-Based Immunotherapy of Cancer

Maruyama¹,

Ishii²,

Tai³

et al. 2012

Advancements in Tumor Immunotherapy and Cancer Vaccines

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Toll-like receptor ligands synergize through distinct dendritic cell pathways to induce T cell responses: Implications for vaccines

Cited by 163 publications

References 49 publications

Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques

Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques

Tumor vaccine composed of CpG ODN class C and irradiated tumor cells up-regulates the expression of genes characteristic of mature dendritic cells and of memory cells

Innate Immunity-Based Immunotherapy of Cancer

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