Influence of saccharide size on the cellular immune response to glycopeptides

Mogemark, Mickael; Cirrito, Thomas P.; Sjölin, Petter; Unanue, Emil R.; Kihlberg, Jan

doi:10.1039/b301747h

Cited by 13 publications

(7 citation statements)

References 46 publications

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“…We also knew from in-depth structural studies of T cell recognition of CD1-glycolipid complexes (24), and functional studies of glycopeptide recognition (25,26), that only small saccharides, from 1 to 4 carbohydrate units, could be accommodated within the binding site of a T cell receptor (TCR) (24), whereas the B cell receptor site could theoretically bind up to 6 units (27). With the only exception of the Cuban anti-H. influenzae vaccine (28), all licensed CVs are produced using purified large natural polysaccharides randomly coupled to a protein carrier (1,29), introducing inherent lot-to-lot variability (29) as well as safety issues.…”

Section: Resultsmentioning

confidence: 99%

T cells control the generation of nanomolar-affinity anti-glycan antibodies

Polonskaya¹,

Deng²,

Sarkar³

et al. 2017

Journal of Clinical Investigation

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Vaccines targeting glycan structures at the surface of pathogenic microbes must overcome the inherent T cell-independent nature of immune responses against glycans. Carbohydrate conjugate vaccines achieve this by coupling bacterial polysaccharides to a carrier protein that recruits heterologous CD4 T cells to help B cell maturation. Yet they most often produce low- to medium-affinity immune responses of limited duration in immunologically fit individuals and disappointing results in the elderly and immunocompromised patients. Here, we hypothesized that these limitations result from suboptimal T cell help. To produce the next generation of more efficacious conjugate vaccines, we have explored a synthetic design aimed at focusing both B cell and T cell recognition to a single short glycan displayed at the surface of a virus-like particle. We tested and established the proof of concept of this approach for 2 serotypes of Streptococcus pneumoniae. In both cases, these vaccines elicited serotype-specific, protective, and long-lasting IgG antibodies of nanomolar affinity against the target glycans in mice. We further identified a requirement for CD4 T cells in the anti-glycan antibody response. Our findings establish the design principles for improved glycan conjugate vaccines. We surmise that the same approach can be used for any microbial glycan of interest.

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Section: Resultsmentioning

confidence: 99%

T cells control the generation of nanomolar-affinity anti-glycan antibodies

Polonskaya¹,

Deng²,

Sarkar³

et al. 2017

Journal of Clinical Investigation

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“…Several publications have indicated that T cells can recognize small saccharides attached to peptides [44]. These T cells are entirely specific, and their role has been postulated in experimental and human rheumatic diseases, particularly by Holmdahl's group [45,46].…”

Section: Post-translational Modificationsmentioning

confidence: 99%

The wide diversity and complexity of peptides bound to class II MHC molecules

Suri

Lovitch

Unanue

2006

Current Opinion in Immunology

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“…The failure of these short glycopeptide antigens to prompt a secondary immune response may be due to their low binding affinity to MHC proteins stemming from a lack of appropriate anchor amino acids [179]. Furthermore, although there is evidence that certain glycopeptides may be presented by MHC molecules, the large glycan is thought to inhibit recognition of the underlying peptide sequences by the TCR [180]. These results indicate that in order to further develop tumor-associated glycopeptide antigens into functional and suitable anti-cancer vaccines, chemical modification is necessary.…”

Section: Synthesis Of Muc1 Glycopeptide Vaccine Conjugates For Selectmentioning

confidence: 96%

Synthetic Glycopeptides from the Mucin Family as Potential Tools in Cancer Immunotherapy

Becker¹,

Dziadek²,

Wittrock³

et al. 2006

CCDT

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Compared to glycoproteins of healthy cells, glycoproteins of tumor cells are often aberrantly glycosylated. Thus, glycopeptide fragments of surface glycoproteins of tumor cells are of interest as tumor-associated antigens for the distinction between normal and tumor cells. Cancer immunotherapy directed at selectively targeting these tumor-associated glycoprotein structure alterations--deficient glycosylation and, thus, exposure of peptide epitopes which are masked in normal cells--is considered a promising approach for the treatment of cancer. For this purpose, glycoproteins from the mucin family are of particular interest. Mucins belong to a class of heavily O-glycosylated, high-molecular weight glycoproteins present on the surface of many epithelial cells. The mucin core protein consists of numerous tandem repeats rich in serine, threonine and proline. In their tumor-associated forms, epithelial mucins carry cryptic saccharide structures such as T(N)-, T-, sialyl-T(N)- and sialyl-T antigens and more complex oligosaccharides (e.g. Lewis(y)). In contrast to glycoproteins isolated from natural sources, synthetic glycopeptides can be obtained in high purity and with exactly defined structure. In this review, methodologies for the synthesis of mucin-type glycopeptides containing complex tumor-associated antigen structures are described. Due to the low immunogenicity often exhibited by synthetic tumor-associated glycopeptide antigens, their conjugation to carrier proteins or suitable T-cell epitopes is essential for the development of anti-tumor vaccines. The results of immunological evaluations of synthetic (glyco)peptides and oligosaccharides are described. Some of these synthetic vaccines show promising activities inducing proliferation of T-cells and cytotoxic T-cell responses.

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Influence of saccharide size on the cellular immune response to glycopeptides

Cited by 13 publications

References 46 publications

T cells control the generation of nanomolar-affinity anti-glycan antibodies

T cells control the generation of nanomolar-affinity anti-glycan antibodies

The wide diversity and complexity of peptides bound to class II MHC molecules

Synthetic Glycopeptides from the Mucin Family as Potential Tools in Cancer Immunotherapy

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