Zwitterionic Polysaccharides Stimulate T Cells with No Preferential Vβ Usage and Promote Anergy, Resulting in Protection against Experimental Abscess Formation

Stingele, Francesca; Corthésy, Blaise; Kusy, Nicole; Porcelli, Steven A.; Kasper, Dennis L.; Tzianabos, Arthur O.

doi:10.4049/jimmunol.172.3.1483

Cited by 54 publications

(58 citation statements)

References 47 publications

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“…In the present study, the immune response to the carrier was found to determine the Ab response to the PS-moiety of this monovalent Pnc1-TT conjugate in young as well as adult mice. Zwitterionic properties of PPS of serotype 1 have been reported to induce T cell stimulation and subsequent apoptosis [46], but do not explain the low T cell responses obtained in neonatal mice, as the TT carrier and not the conjugate, was used for in vitro stimulation. We have previously found that in vitro stimulation of spleen cells with native PPS-1 induces neither proliferation nor cytokine secretion in Pnc1-TT immunized young or adult mice (data not shown).…”

Section: Discussionmentioning

confidence: 98%

Early life T cell responses to pneumococcal conjugates increase with age and determine the polysaccharide‐specific antibody response and protective efficacy

et al. 2006

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Immunization with a tetanus-protein (TT) pneumococcal polysaccharide (PPS) conjugate vaccine (Pnc1-TT) induces protective immunity against lethal pneumococcal infections in neonatal and infant mice, but anti-PPS IgG response and protective efficacy is lower than in adult mice. Here, we show that reduced antibody (Ab) response and protection against infections is directly related to impaired T cell response to the carrier. Whereas spleen cells from adult mice immunized with Pnc1-TT responded with proliferation and IFN-gamma secretion to in vitro stimulation with TT, spleen cells from neonatal and infant mice did not. However, significant, but age dependent, Th2-cytokine responses were observed in mice immunized with Pnc1-TT. Impaired IFN-gamma production upon TT-stimulation in vitro was also reflected in reduced IFN-gamma/IL-5 ratio. The IL--5 response correlated with IgG anti-PPS titers, and the lack of PPS Ab in the majority of neonatal mice was clearly associated with absence of carrier-specific IL-5 production. These results show that immunization with Pnc1-TT induces carrier-specific T cell responses that increase with age and determine the levels of PPS-specific Ab elicited. Whereas a weak and Th2-biased response was observed in neonatal mice, infant mice showed a mixed Th1-Th2 response as observed in adults

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Section: Discussionmentioning

confidence: 98%

Early life T cell responses to pneumococcal conjugates increase with age and determine the polysaccharide‐specific antibody response and protective efficacy

et al. 2006

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“…Here, we show that rational chemical modification can be used to produce a glycoconjugate vaccine in which the PS Ag has acquired additional adjuvant properties. This work is based on previous findings showing that natural ZPS, such as PSA, activate T cells and APCs (7,8,12). Because this biological activity depends on the zwitterionic structure of this capsular PS (20)(21)(22), we generated a similar charge motif in a vaccine candidate PS by the chemical introduction of positive charges into the naturally anionic capsular PS of GBS (16).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Toll-like receptor 2 (TLR2) has been identified as the receptor implicated in the activation of APCs induced by PSA (11). Because PSA injected in a rat abscess model induces protection against the bacterium (12), the use of ZPS that combine Ag and adjuvant properties in the same molecule may represent a strategy for vaccine design. Moreover, a number of vaccine candidates consisting of protein Ag fused to synthetic lipopeptides targeting TLR2 have been proposed in the past.…”

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confidence: 99%

Toll-like receptor 2 dependent immunogenicity of glycoconjugate vaccines containing chemically derived zwitterionic polysaccharides

Gallorini

Mancuso

Cozzi

et al. 2009

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

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Group B Streptococcus (GBS) causes serious infection in neonates and is an important target of vaccine development. Zwitterionic polysaccharides (ZPS), obtained through chemical introduction of positive charges into anionic polysaccharides (PS) from GBS, have the ability to activate human and mouse antigen presenting cells (APCs) through toll-like receptor 2 (TLR2).To generate a polysaccharide vaccine with antigen (Ag) and adjuvant properties in one molecule, we have conjugated ZPS with a carrier protein. ZPS-glycoconjugates induce higher T-cell and Ab responses to carrier and PS, respectively, compared to control PS-glycoconjugates made with the native polysaccharide form. The increased immunogenicity of ZPS-conjugates correlates with their ability to activate dendritic cells (DCs). Moreover, protection of mothers or neonate offspring from lethal GBS challenge is better when mothers are immunized with ZPS-conjugates compared to immunization with PS-conjugates. In TLR2 knockout mice, ZPS-conjugates lose both their increased immunogenicity and protective effect after vaccination. When ZPS are coadministered as adjuvants with unconjugated tetanus toxoid (TT), they have the ability to increase the TT-specific antibody titer. In conclusion, glycoconjugates containing ZPS are potent vaccines. They target Ag to TLR2-expressing APCs and activate these APCs, leading to better T-cell priming and ultimately to higher protective Ab titers. Thus, rational chemical design can generate potent PS-adjuvants with wide application, including glycoconjugates and coadministration with unrelated protein Ags.adjuvant ͉ dendritic cell ͉ Group B Streptococcus C lassically, capsular polysaccharides (PS) from bacteria are considered to be T-independent Ags (1) able to activate B cells directly, without a contribution of help by CD4 ϩ T cells. Therefore, the immune response to PS fails to induce significant and prolonged titers of antibody with high avidity in infants and persistent Agspecific memory B cells in adults. For this reason, in vaccines, PS are mostly used conjugated with a carrier protein that provides T-cell help and consequently immunological memory (2). Glycoconjugate vaccines against the Gram-positive bacterium Group B Streptococcus (GBS) have been shown to confer serotype specific protection in mice and have been tested in clinical trials (3). In humans, addition of alum to the vaccine formulation did not further increase the immune response induced (4). In contrast, in animal models, adsorption to Al(OH) 3 (alum) enhances the immunogenicity of the glycoconjugate (5, 6) which may be explained by the possibility that animals are more naive to GBS than humans. Moreover, a number of commercially available glycoconjugate vaccines, such as those against Meningococcus C, Haemophilus influenza, and the 7-valent Pneumococcus vaccine, use alum or aluminium phosphate as an adjuvant. Thus, the combination of glycoconjugates with adjuvants likely generates potent vaccines, able to activate APCs and induce strong Ag-specific T and B c...

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“…This complex has a zwitterion nature (Stingele et al 2004) and a critical involvement in abscess formation (Coyne et al 2000). B. fragilis can modulate its surface antigenicity (phase dependent) and it has at least eight distinct polysaccharides (PSA to PSH) (Krinos et al 2001).…”

Section: Discussionmentioning

confidence: 99%

“…B. fragilis can modulate its surface antigenicity (phase dependent) and it has at least eight distinct polysaccharides (PSA to PSH) (Krinos et al 2001). It is well documented that the CPC is involved in abscess formation (Stingele et al 2004). This capsule modulation (Krinus et al 2001) may be used as a strategy to help the bacteria evade the host immune system and at the same time to colonise the host.…”

mentioning

confidence: 99%

The redox potential interferes with the expression of laminin binding molecules in Bacteroides fragilis

Ferreira¹,

Yates

Goldner

et al. 2008

Mem. Inst. Oswaldo Cruz

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The Bacteroides fragilis ATCC strain was grown in a synthetic media with contrasting redox potential (Eh) levels [reduced (-60 mV) Key words: Bacteroides fragilis -adhesion -redox potential -laminin binding proteins -outer membrane proteinsBacteroides fragilis is a Gram-negative obligate anaerobic bacterium and a common member of the human microbiota (Jousiemies-Somier 2002), but it is also an important opportunistic pathogen. This bacterium is the most frequently isolated anaerobic species from human intra-abdominal infections, and this represents a serious clinical problem, especially when abscesses are formed (Finegold 1995). Although several factors have been described, the pathogenicity of this microorganism is still not completely understood. The capsular polysaccharide complex (CPC) is a crucial factor in the virulence potential of the species (Comstock et al. 1999, Coyne et al. 2000. B. fragilis modulates its surface antigenicity, generating distinct CPC combinations (Krinos et al. 2001). High variation in the polysaccharide expression of B. fragilis has already been demonstrated using monoclonal antibodies (Patrick et al. 1999). Recent analyses of the genome sequences revealed DNA inversion regions. These results suggested that the ability of B. fragilis to colonise several host environments, behaving either as a member of the microbiota or a pathogen, might be linked to switching of polysaccharide biosynthesis (Krinos et al. 2001).The extracellular matrix (ECM) is a stable macromolecular structure underlying epithelial and endothelial cells and surrounding connective tissue cells. In the ECM, collagens, proteoglycans and structural glycoproteins, such as fibronectin and laminin, are found and these molecules are usually exploited for colonisation by microbes (Ljungh et al. 1996). The cell surface adhesins that mediate such recognition are termed "microbial surface components recognising adhesive matrix molecules" (MSCRAMMS). In the past, several microorganisms have been shown to express these molecules (Ljungh at al. 1996, Lähtennmaki et al. 1998, Crago & Koronakis 1999.Many bacterial virulence factors are well regulated with their expression linked to several environmental signals, such as temperature, pH, osmolarity, carbon source and iron levels (Sijbrandi et al. 2005). To the obligate anaerobic bacteria, the redox potential (Eh) represents an important environmental parameter to their survival. It has been shown that, when grown at different Eh levels, B. fragilis can change its state from commensal to pathogenic, becoming invasive to HeLa cells (Goldner et al. 1993).In the present investigation, we searched for B. fragilis properties regulated by Eh. We investigated interference with adhesion to ECM components and with the expression of proteins and surface polysaccharides. Our results showed that the adhesion to laminin is influenced by Eh, and we report that several putative binding proteins were more highly expressed under oxidising conditions by ATCC 43859 strain. MATERIAL AND METHODSBacter...

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Zwitterionic Polysaccharides Stimulate T Cells with No Preferential Vβ Usage and Promote Anergy, Resulting in Protection against Experimental Abscess Formation

Cited by 54 publications

References 47 publications

Early life T cell responses to pneumococcal conjugates increase with age and determine the polysaccharide‐specific antibody response and protective efficacy

Early life T cell responses to pneumococcal conjugates increase with age and determine the polysaccharide‐specific antibody response and protective efficacy

Toll-like receptor 2 dependent immunogenicity of glycoconjugate vaccines containing chemically derived zwitterionic polysaccharides

The redox potential interferes with the expression of laminin binding molecules in Bacteroides fragilis

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