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Parameters Underlying Distinct T Cell-Dependent Polysaccharide-Specific IgG Responses to an Intact Gram-Positive Bacterium versus a Soluble Conjugate Vaccine¹

Jesus Colino^*, Gouri Chattopadhyay^*, Goutam Sen, Quanyi Chen^*, Andrew Lees, David H. Canaday, Anatoly Rubtsov^¶, Raul Torres^¶ and Clifford M. Snapper^2,*

^* Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD 20852; Fina BioSolutions, Rockville, MD 20850; Geriatric Research, Education, and Clinical Center, Cleveland, OH 44106; and ^¶ University of Colorado and National Jewish Health, Integrated Department of Immunology, Denver, CO 80206

IgG anti-polysaccharide (PS) responses to both intact Streptococcus pneumoniae (Pn) and PS conjugate vaccines are dependent on CD4⁺ T cells, B7-dependent costimulation, and CD40-CD40-ligand interactions. Nevertheless, the former response, in contrast to the latter, is mediated by an ICOS-independent, apoptosis-prone, extrafollicular pathway that fails to generate PS-specific memory. We show that pre-existing PS-specific Igs, the bacterial surface or particulation, selective recruitment of B cell subsets, or activation and recruitment of Pn protein-specific CD4⁺ T cells do not account for the failure of Pn to generate PS-specific IgG memory. Rather, the data suggest that the critical factor may be the lack of covalent attachment of PS to protein in intact Pn, highlighting the potential importance of the physicochemical relationship of PS capsule with the underlying bacterial structure for in vivo induction of PS-specific Igs.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by National Institutes of Health Grant 2R01 AI49192 and the United States Uniformed Services University of the Health Sciences Dean’s Research and Education Endowment Fund.

² Address correspondence and reprint requests to Dr. Clifford M. Snapper, Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814. E-mail address: csnapper{at}usuhs.mil

³ Abbreviations used in this paper: Pn, intact Streptococcus pneumoniae; Pn14, intact Pn, capsular type 14; PS, polysaccharide; PPS14, pneumococcal polysaccharide, capsular type 14; PspA, pneumococcal surface protein A; R36Ach, unencapsulated variant of Pn, capsular type 2 (strain D39) depleted of choline-binding proteins; TD, T cell-dependent; TI, T cell-independent; USUHS, United States Uniformed Services University of the Health Sciences; PC, phosphorylcholine; CBP, choline-binding protein; MHC-II, MHC class II; MSA, mouse serum albumin; CpG-ODN, CpG-containing oligodeoxynucleotide; BMDC, bone marrow dendritic cell; MZ, marginal zone; MZB, MZ B cell; FB, follicular B cell; WT, wild type.