Bacterial Flagellin Is an Effective Adjuvant for CD4+ T Cells In Vivo

McSorley, Stephen J.; Ehst, Benjamin D.; Yu, Yimin; Gewirtz, Andrew T.

doi:10.4049/jimmunol.169.7.3914

Cited by 237 publications

(188 citation statements)

References 45 publications

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“…This observation helps explain previous reports regarding the high antigenicity and adjuvant activity of bacterial flagellin (47). Our results demonstrate that TLR5 is expressed on human iDCs and that these cells are sensitive to flagellin stimulation, consistent with other reports demonstrating TLR5 expression in human monocytes and iDCs by Northern blot and RT-PCR analysis (37,38,48).…”

Section: Discussionsupporting

confidence: 82%

“…Besides providing a control for the purity of our fliC preparation, this seems at odds with the recent findings by McSorley et al (47) demonstrating the ability of bacterial flagellin to effectively elicit a robust CD4 T cell response in vivo. Though our in vitro findings predict flagellin will not directly stimulate DC maturation in vivo, it is still possible that other cells, such as skin epithelia and gut epithelia, which express TLR5 (Fig.…”

Section: Discussioncontrasting

confidence: 48%

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The Toll-Like Receptor 5 Stimulus Bacterial Flagellin Induces Maturation and Chemokine Production in Human Dendritic Cells

Means

Hayashi

Smith

et al. 2003

The Journal of Immunology

363

277

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Toll-like receptors (TLRs) are pattern recognition receptors that serve an important function in detecting pathogens and initiating inflammatory responses. Upon encounter with foreign Ag, dendritic cells (DCs) go through a maturation process characterized by an increase in surface expression of MHC class II and costimulatory molecules, which leads to initiation of an effective immune response in naive T cells. The innate immune response to bacterial flagellin is mediated by TLR5, which is expressed on human DCs. Therefore, we sought to investigate whether flagellin could induce DC maturation. Immature DCs were cultured in the absence or presence of flagellin and monitored for expression of cell surface maturation markers. Stimulation with flagellin induced increased surface expression of CD83, CD80, CD86, MHC class II, and the lymph node-homing chemokine receptor CCR7. Flagellin stimulated the expression of chemokines active on neutrophils (IL-8/CXC chemokine ligand (CXCL)8, GRO-α/CXCL1, GRO-β/CXCL2, GRO-γ/CXCL3), monocytes (monocyte chemoattractant protein-1/CC chemokine ligand (CCL)2), and immature DCs (macrophage-inflammatory protein-1α/CCL3, macrophage-inflammatory protein-1β/CCL4), but not chemokines active on effector T cells (IFN-inducible protein-10 kDa/CXCL10, monokine induced by IFN-γ/CXCL9, IFN-inducible T cell α chemoattractant/CXCL11). However, stimulating DCs with both flagellin and IFN-inducible protein-10 kDa, monokine induced by IFN-γ, and IFN-inducible T cell α chemoattractant expression, whereas stimulation with IFN-β or flagellin alone failed to induce these chemokines. In functional assays, flagellin-matured DCs displayed enhanced T cell stimulatory activity with a concomitant decrease in endocytic activity. Finally, DCs isolated from mouse spleens or bone marrows were shown to not express TLR5 and were not responsive to flagellin stimulation. These results demonstrate that flagellin can directly stimulate human but not murine DC maturation, providing an additional mechanism by which motile bacteria can initiate an acquired immune response.

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Section: Discussionsupporting

confidence: 82%

Section: Discussioncontrasting

confidence: 48%

The Toll-Like Receptor 5 Stimulus Bacterial Flagellin Induces Maturation and Chemokine Production in Human Dendritic Cells

Means

Hayashi

Smith

et al. 2003

The Journal of Immunology

363

277

View full text Add to dashboard Cite

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“…Other cell types, including monocytes, respond to flagellin inducing the production of proinflammatory cytokines (31). Furthermore, flagellin plays a role in triggering adaptive immune responses by stimulating chemokine secretion and migration and maturation of dendritic cells (32,33), and by modulating T cell activation in vivo (34). Flagellin is the ligand of TLR-5 (35,36), although additional receptors may modulate signaling (37,38).…”

mentioning

confidence: 99%

Pseudomonas aeruginosa Flagellin and Alginate Elicit Very Distinct Gene Expression Patterns in Airway Epithelial Cells: Implications for Cystic Fibrosis Disease

Cobb

Mychaleckyj

Wozniak

et al. 2004

The Journal of Immunology

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Infection with the opportunistic pathogen Pseudomonas aeruginosa remains a major health concern. Two P. aeruginosa phenotypes relevant in human disease include motility and mucoidy. Motility is characterized by the presence of flagella and is essential in the establishment of acute infections, while mucoidy, defined by the production of the exopolysaccharide alginate, is critical in the development of chronic infections, such as the infections seen in cystic fibrosis patients. Indeed, chronic infection of the lung by mucoid P. aeruginosa is a major cause of morbidity and mortality in cystic fibrosis patients. We have used Calu-3 human airway epithelial cells to investigate global responses to infection with motile and mucoid P. aeruginosa. The response of airway epithelial cells to exposure to P. aeruginosa motile strains is characterized by a specific increase in gene expression in pathways controlling inflammation and host defense. By contrast, the response of airway epithelia to the stimuli presented by mucoid P. aeruginosa is not proinflammatory and, hence, may not be conducive to the effective elimination of the pathogen. The pattern of gene expression directed by flagellin, but not alginate, includes innate host defense genes, proinflammatory cytokines, and chemokines. By contrast, infection with alginate-producing P. aeruginosa results in an overall attenuation of host responses and an antiapoptotic effect.

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“…Flagellin, the protein component of bacterial flagella which aids bacterial mobility, is an agonist for TLR5 and is a potent adjuvant in mice, as well as cynomolgus and African green monkeys [21][22][23]. Pseudomonas aeruginosa, a Gram negative bacterium and opportunistic pathogen is a major cause of morbidity and mortality in cystic fibrosis (CF) patients.…”

Section: Tlr5mentioning

confidence: 99%

TLR, NLR Agonists, and Other Immune Modulators as Infectious Disease Vaccine Adjuvants

Higgins

Mills

2010

Curr Infect Dis Rep

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Vaccines based on attenuated or killed viruses and bacteria are highly effective in preventing infection with a range of pathogens, but can have safety issues. Therefore, there is a move towards subunit vaccines based on recombinant proteins or naked DNA. However, protein subunit vaccines are typically poorly immunogenic when administered alone and therefore require co-administration with adjuvants to boost the immune response.

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Bacterial Flagellin Is an Effective Adjuvant for CD4+ T Cells In Vivo

Cited by 237 publications

References 45 publications

The Toll-Like Receptor 5 Stimulus Bacterial Flagellin Induces Maturation and Chemokine Production in Human Dendritic Cells

The Toll-Like Receptor 5 Stimulus Bacterial Flagellin Induces Maturation and Chemokine Production in Human Dendritic Cells

Pseudomonas aeruginosa Flagellin and Alginate Elicit Very Distinct Gene Expression Patterns in Airway Epithelial Cells: Implications for Cystic Fibrosis Disease

TLR, NLR Agonists, and Other Immune Modulators as Infectious Disease Vaccine Adjuvants

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