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Polysaccharide Structure Dictates Mechanism of Adaptive Immune

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Polysaccharide Structure Dictates Mechanism of Adaptive Immune Polysaccharide structure dictates mechanism of SEE COMMENTARY adaptive immune response to glycoconjugate vaccines Ximei Suna,b, Giuseppe Stefanettia,c, Francesco Bertid, and Dennis L. Kaspera,1 aDepartment of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; bGraduate Program in Immunology, Harvard Medical School, Boston, MA 02115; cDepartment of Chemistry, University of Milan, 20133 Milan, Italy; and dTechnical R&D, GSK Vaccines, 53100 Siena, Italy Contributed by Dennis L. Kasper, November 1, 2018 (sent for review September 25, 2018; reviewed by Peter R. Andreana and Moriya Tsuji) Glycoconjugate vaccines are among the most effective interven- peptide from the carrier (5). These surface-presented CPSs are + tions for preventing several serious infectious diseases. Covalent able to activate a subset of CD4 T cells, designated carbohydrate- linkage of the bacterial capsular polysaccharide to a carrier protein specific T cells (Tcarbs), which regulate the adaptive immune + provides CD4 T cells with epitopes that facilitate a memory re- response to the GBSIII glycoconjugate (5–8). Similar mechanisms sponse to the polysaccharide. Classically, the mechanism responsi- have now been shown to be responsible for T helper responses to ble for antigen processing was thought to be similar to what was glycoconjugates made with the type 3 S. pneumoniae poly- known for hapten-carrier conjugates: protease digestion of the saccharide (Pn3P) (6). carrier protein in the endosome and presentation of a resulting + In the present study, we analyze the T cell response to gly- peptide to the T cell receptor on classical peptide-recognizing CD4 coconjugates of several other important pathogens, including T cells. Recently, an alternative mechanism has been shown to be conjugates made from Vi antigen of Salmonella Typhi (Vi), the responsible for the memory response to some glycoconjugates. Pro- H. cessing of both the protein and the polysaccharide creates glycopep- CPS of type Ib group B streptococci (GBSIb), the CPS of tides in the endosome of antigen-presenting cells. For presentation, influenzae type b (Hib), and the group C polysaccharide of N. the peptide portion of the glycopeptide is bound to MHCII, allowing meningitidis (MenC). We report that only MenC-specific IgG the covalently linked glycan to activate carbohydrate-specific helper responses are not regulated by Tcarbs. This lack of Tcarb acti- + CD4 T cells (Tcarbs). Herein, we assessed whether this same mech- vation is related to the structure of the polysaccharide. De- anism applies to conjugates prepared from other capsular polysac- polymerization of MenC polysaccharide in the acidic environment INFLAMMATION IMMUNOLOGY AND charides. All of the glycoconjugates tested induced Tcarb-dependent of the endolysosome results in marked reduction in polysaccha- responses except that made with group C Neisseria meningitidis;in ride size to monomers, with a consequent failure to be recognized the latter case, only peptides generated from the carrier protein by T cells as an independent antigen. Given that there may be were critical for helper T cell recognition. Digestion of this acid- at least two mechanisms governing T cell responses to glyco- sensitive polysaccharide, a linear homopolymer of α(2 → 9)-linked conjugates, a deeper understanding of factors influencing anti- sialic acid, to the size of the monomeric unit resulted in a dominant + gen processing and presentation as well as cooperation between CD4 T cell response to peptides in the context of MHCII. Our results T and B cells in response to glycoconjugate vaccination is a key show that different mechanisms of presentation, based on the struc- factor to be considered in improving the design of the next- ture of the carbohydrate, are operative in response to different generation glycoconjugate vaccines. glycoconjugate vaccines. glycoconjugate | vaccine | Tcarb | antigen presentation | group C Neisseria Significance meningitidis Helper T cell responses to glycoconjugate vaccines are regu- lated through mechanisms dependent upon the structure of any pathogenic bacteria express large-molecular-sized the polysaccharide. We show that three of the four important surface carbohydrates called capsular polysaccharides M conjugate vaccines tested induced antibody responses regulated (CPSs). Beginning in the 1980s, CPSs of bacterial targets were primarily by carbohydrate-recognizing helper T cells. However, coupled to carrier proteins to create effective glycoconjugate the adaptive immune response to meningococcal group C (MenC) vaccines. These vaccines were more immunogenic than un- conjugate was restricted to peptide-recognizing helper T cells. conjugated polysaccharides, especially in children under 2 y of We show that MenC is degraded to a monomeric sialic acid res- age (1). Several glycoconjugate vaccines were developed and idue that cannot be recognized by T cell receptor as an inde- have played an enormous role in preventing infectious dis- pendent antigen. The structure of the saccharide constitutes a eases caused by virulent pathogens, including vaccines against critical factor in determining the processing and presentation of Haemophilus influenzae type b, Streptococcus pneumoniae, and glycoconjugate vaccines. An understanding of the mechanisms Neisseria meningitidis (2, 3). On the basis of studies of hapten- underlying the immune responses to glycoconjugates will be carrier immune responses, it had been assumed that, in glyco- crucial in the production of highly protective knowledge-based conjugate vaccines, the peptide processed from the carrier pro- vaccines. tein is presented by the major histocompatibility class II (MHCII) molecule and that this signal plays a central role in Author contributions: X.S. and D.L.K. designed research; X.S. performed research; G.S. and + activating CD4 helper T cells. The peptide-recognizing T cells F.B. contributed new reagents/analytic tools; X.S. and D.L.K. analyzed data; and X.S., G.S., in turn help B cell maturation and the formation of immuno- F.B., and D.L.K. wrote the paper. logicmemory(4).Theoriginalhypothesis was in part based Reviewers: P.R.A., University of Toledo; and M.T., Aaron Diamond AIDS Research Center. on the failure of pure polysaccharides to elicit IgM-to-IgG The authors declare no conflict of interest. class switching and substantial memory responses. Recently, we Published under the PNAS license. reported a different mechanism governing the immune responses See Commentary on page 14. to glycoconjugate vaccines, using the CPS of type III group B 1To whom correspondence should be addressed. Email: [email protected]. Streptococcus (GBSIII) as a model antigen. We showed that This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. antigenic fragments of the polysaccharide are presented on the 1073/pnas.1816401115/-/DCSupplemental. surface by MHCII molecules in the context of a covalently linked Published online December 3, 2018. www.pnas.org/cgi/doi/10.1073/pnas.1816401115 PNAS | January 2, 2019 | vol. 116 | no. 1 | 193–198 Downloaded by guest on September 24, 2021 Results Various Glycoconjugates Induce T Helper Cells Recognizing Different Epitopes. We had previously shown that a clear biomarker for Tcarb-dependent responses was a polysaccharide-specific anti- body response after priming with a polysaccharide covalently linked to a carrier protein and boosting with the same poly- saccharide linked to a different and unrelated carrier protein. To investigate the involvement of Tcarbs in the humoral immune response to different glycoconjugates, we performed priming and boosting immunization experiments with glycoconjugates made with Vi, GBSIb, Hib, and MenC CPSs. BALB/c mice were primed at the beginning of the experiment and boosted 14 d later with different antigen combinations. One week after the boost, serum levels of polysaccharide-specific IgG were determined. For Vi, GBSIb, and Hib glycoconjugates, boosting with a gly- coconjugate containing the same polysaccharide but a heterolo- gous carrier protein induced polysaccharide-specific IgG titers of the same magnitude as those seen after priming and boosting with glycoconjugates containing the same carrier (Fig. 1A). As reported with GBSIII and Pn3P (5, 6), this result supports a Tcarb- dependent mechanism for all three of these glycoconjugates. In marked contrast to the above results, priming and boosting with MenC glycoconjugates containing heterologous carrier proteins induced significantly lower levels of MenC-specific IgG than did primary and secondary immunization with either a MenC-OVA (ovalbumin) conjugate or a MenC-CRM197 (non- toxic mutant of diphtheria toxin) conjugate. This result was confirmed with a combination of different carriers, including MenC-TT (tetanus toxoid), MenC-HEL (hen egg lysozyme), MenC-OVA, and MenC-CRM197 (Fig. 1B). We also found that MenC-specific IgM levels were similar in groups immunized with different conjugate combinations, a result suggesting a similar level of B cell activation independent of the carrier (SI Ap- pendix,Fig.S1A). To exclude the possibility that we were seeing a T cell-independent response, we treated mice with CD4-specific blocking antibody during the interval between priming and boosting with MenC-CRM197. The excellent booster IgG response observed in mice treated with isotype control antibody was sig- nificantly reduced in mice treated with anti-CD4 (SI Appendix, Fig. S1B). The failure of MenC conjugates
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