HIV Gag protein conjugated to a Toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8<sup>+</sup>T cell responses in nonhuman primates

Wille-Reece, Ulrike; Flynn, Barbara J.; Loré, Karin; Koup, Richard A.; Kedl, Ross M.; Mattapallil, Joseph J.; Weiss, Walter R.; Roederer, Mario; Seder, Robert A.

doi:10.1073/pnas.0507484102

Cited by 300 publications

(252 citation statements)

References 32 publications

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“…First, TLRs trigger the secretion of critical cytokines such as IL1, IL-6 and IL-12 by DCs, which are important for T-cell differentiation and the induction of potent adaptive immunity. Several groups have shown that conjugation of certain TLR ligands (that is, for TLR2, TLR4, TLR7 and TLR9) to peptides or proteins significantly enhances CD4 þ and CD8 þ T-cell responses compared with administration of TLR ligands or a peptide/protein mixture alone (Jackson et al, 2004;Wille-Reece et al, 2005;Blander and Medzhitov, 2006). Third, TLRs can directly stimulate the proliferation of CD4 þ and CD8 þ T cells as well as reverse the suppressive function of Treg cells (Crellin et al, 2005;Peng et al, 2005;Tabiasco et al, 2006).…”

Section: Targeting Tlrs For Cancer Therapymentioning

confidence: 99%

Toll-like receptors and immune regulation: implications for cancer therapy

2008

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Section: Targeting Tlrs For Cancer Therapymentioning

confidence: 99%

Toll-like receptors and immune regulation: implications for cancer therapy

2008

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“…[201][202][203] Intracellular TLR9 Activation: CpG ds-DNA Unmethylated "CpG motifs" which are present at high frequency in bacterial but not mammalian DNA due to a combination of Gag-specific CD8 + CTL responses compared with animals immunized with HIV Gag protein and the TLR7 agonist as a noncovalent mixture. 173 It must be noted, however, the method of conjugation in the above-referenced study was by UV irradiation of antigenimidazoquinoline mixtures, followed by exhaustive dialysis. 173 There are no photoactivable groups on the molecule, and it is not clear whether proteins can be truly covalently modified with UV irradiation alone, and it would be preferable to introduce biocompatible electrophiles such as the isothiocyanate group [174][175][176] or succinimidyl esters, [177][178][179] with a linker, so that formal, covalent adduction with protein antigens can be performed under aqueous conditions.…”

Section: Intracellular Tlr7 Activation: Imidazoquinoline Ligandsmentioning

confidence: 99%

“…173 It must be noted, however, the method of conjugation in the above-referenced study was by UV irradiation of antigenimidazoquinoline mixtures, followed by exhaustive dialysis. 173 There are no photoactivable groups on the molecule, and it is not clear whether proteins can be truly covalently modified with UV irradiation alone, and it would be preferable to introduce biocompatible electrophiles such as the isothiocyanate group [174][175][176] or succinimidyl esters, [177][178][179] with a linker, so that formal, covalent adduction with protein antigens can be performed under aqueous conditions. A number of preclinical studies with TLR7 agonists as adjuvants are currently in progress.…”

Section: Intracellular Tlr7 Activation: Imidazoquinoline Ligandsmentioning

confidence: 99%

Potential adjuvantic properties of innate immune stimuli

et al. 2009

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Just as the prescient comment by Gaston Ramon was relegated to the last footnote of his 1926 paper, 1 so has research on the mechanisms of action of adjuvants, until recently, languished as parenthetical annotations and addenda in the archives of immunology and vaccine development. Ramon defined immunological adjuvants as "substances used in combination with a specific antigen that produced a more robust immune response than the antigen alone." Interestingly enough, he was referring to his empirical findings that the addition of bread crumbs, tapioca, saponin and 'starch oil' to antigenic preparations greatly enhanced antibody responses to diphtheria or tetanus. 2 A year later, the adjuvanticity of aluminum salts (primarily phosphate and hydroxide) was discovered by Glenny and coworkers. 3 In the 83 years that have elapsed, the repertoire of investigational adjuvants has grown to encompass a very wide range of materials, 4 but aluminum salt-based mineral salts (generically, and incorrectly, termed "alum") have remained the only adjuvants currently approved by the FDA. Aluminum salts have enjoyed a good safety record, but they are weak adjuvants for antibody induction and induce a T helper-2 (T H 2)-skewed, rather than a T helper-1 (T H 1) response. 5,6 Furthermore, not only are aluminum salts ineffective at inducing cytotoxic T lymphocyte (CTL) or mucosal IgA antibody responses, but also have a propensity to induce IgE responses, which have been associated with allergic reactions in some subjects. 5,6 Very recent reports implicate the Nalp3 inflammasome, a component of the innate immune response, as the effector limb of alum-associated adjuvanticity. [7][8][9] In 1962, Dresser observed that injection of purified soluble proteins not only failed to stimulate an immune response, but tolerized animals unless a bacterial extract was admixed with the protein immunogen. 10 This led him to redefine adjuvanticity as "a property of a substance which can act as a physiological switch, directing at least some immunologically competent cells to respond by making antibody rather than by becoming immunologically paralyzed by the antigen," 11 confirming Johnson's earlier observations that lipopolysaccharide (LPS) from Gram-negative bacteria exerted potent adjuvant properties, 12 and perhaps paved the way for the subsequent discovery of the wide range of microorganism-derived adjuvants. 13 TLRs are pattern recognition receptors present on diverse cell types that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). 14,15 There are 10 TLRs in the human genome;

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“…This finding suggested that CD8 ϩ DC possess specialized machinery for cross-presentation that is expressed poorly, if at all, by other DC subsets. We therefore hypothesized that the role of different DC subsets in crosspresentation is determined by their antigen-handling properties.Understanding whether the capacity to cross-present is dictated by antigen capture or handling is important for the design of vaccination strategies based on antigen targeting in vivo (15)(16)(17)(18)(19). For instance, if all of the DC subsets can cross-present, a vaccine antigen targeted to a receptor shared by all subsets might be cross-presented by all DC.…”

mentioning

confidence: 99%

The dominant role of CD8⁺dendritic cells in cross-presentation is not dictated by antigen capture

Schnorrer¹,

Behrens²,

Wilson

et al. 2006

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

349

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Mouse spleens contain three populations of conventional (CD11c high ) dendritic cells (DCs) that play distinct functions. The CD8 ؉ DC are unique in that they can present exogenous antigens on their MHC class I molecules, a process known as cross-presentation. It is unclear whether this special ability is because only the CD8 ؉ DC can capture the antigens used in cross-presentation assays, or because this is the only DC population that possesses specialized machinery for cross-presentation. To solve this important question we examined the splenic DC subsets for their ability to both present via MHC class II molecules and cross-present via MHC class I using four different forms of the model antigen ovalbumin (OVA). These forms include a cell-associated form, a soluble form, OVA expressed in bacteria, or OVA bound to latex beads. With the exception of bacterial antigen, which was poorly cross-presented by all DC, all antigenic forms were cross-presented much more efficiently by the CD8 ؉ DC. This pattern could not be attributed simply to a difference in antigen capture because all DC subsets presented the antigen via MHC class II. Indeed, direct assessments of endocytosis showed that CD8 ؉ and CD8 ؊ DC captured comparable amounts of soluble and bead-associated antigen, yet only the CD8 ؉ DC cross-presented these antigenic forms. Our results indicate that cross-presentation requires specialized machinery that is expressed by CD8 ؉ DC but largely absent from CD8 ؊ DC. This conclusion has important implications for the design of vaccination strategies based on antigen targeting to DC.antigen presentation ͉ mice ͉ endocytosis ͉ ovalbumin ͉ vaccines D endritic cells (DC) possess several mechanisms that make them highly efficient antigen-presenting cells. DC can endocytose a large variety of exogenous antigens for presentation via MHC class II molecules and for cross-presentation via MHC class I (1). The cross-presenting capacity of DC is unusual, because most other cell types are only able to present endogenous antigens (i.e., antigens synthesized by the antigenpresenting cells themselves) on their MHC class I molecules. Thus, DC possess specialized machinery, as yet not fully defined, that allows delivery of exogenous antigens into the MHC class I presentation pathway for cross-presentation (2, 3).On the other hand, several populations of DC have been described (4, 5), and it is unclear whether all these DC types can cross-present (6). Mouse spleens contain three ''conventional'' (CD11c high ) DC subsets: CD8 ϩ DC, CD4 ϩ DC, and CD4 Ϫ CD8 Ϫ [double negative (DN)] DC. Previous studies have shown that cell-associated antigen was cross-presented by CD8 ϩ but not CD8 Ϫ DC (7-10). The unique capacity of the CD8 ϩ DC at cross-presenting this form of antigen was attributed to their ability to capture dead cells (7-9, 11, 12) because antigens in soluble or immunocomplexed form, or associated to bacteria, were reportedly cross-presented by both CD8 ϩ and CD8 Ϫ DC (8, 9, 13). These findings led to the hypothesis that all DC can...

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HIV Gag protein conjugated to a Toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8⁺T cell responses in nonhuman primates

Abstract: vaccine ͉ dendritic cell ͉ cross-presentation ͉ cellular immunity

Cited by 300 publications

References 32 publications

Toll-like receptors and immune regulation: implications for cancer therapy

Toll-like receptors and immune regulation: implications for cancer therapy

Potential adjuvantic properties of innate immune stimuli

The dominant role of CD8⁺dendritic cells in cross-presentation is not dictated by antigen capture

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HIV Gag protein conjugated to a Toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8+T cell responses in nonhuman primates

Abstract: vaccine ͉ dendritic cell ͉ cross-presentation ͉ cellular immunity

Cited by 300 publications

References 32 publications

Toll-like receptors and immune regulation: implications for cancer therapy

Toll-like receptors and immune regulation: implications for cancer therapy

Potential adjuvantic properties of innate immune stimuli

The dominant role of CD8+dendritic cells in cross-presentation is not dictated by antigen capture

Contact Info

Product

Resources

About

HIV Gag protein conjugated to a Toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8⁺T cell responses in nonhuman primates

The dominant role of CD8⁺dendritic cells in cross-presentation is not dictated by antigen capture