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

Abstract

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.

Distinct Mechanisms Underlie Boosted Polysaccharide-Specific IgG Responses Following Secondary Challenge with Intact Gram-Negative versus Gram-Positive Extracellular Bacteria

“…This is consistent with the augmented MCPS-specific IgG response observed in MenC-primed mice following booster immunization with isolated MCPS, also a TI Ag, or a soluble covalent conjugate of MCPS and TT. Results similar to that obtained with MenC are also observed using another GN bacteria, A. baumannii expressing PNAG, that is, a primary PNAG-specific IgG response that peaks relatively late (by day [14][15][16][17][18][19][20][21] and that is independent of CD4 + T cells, and an augmented PNAG-specific IgG response following booster immunization with A. baumannii that requires CD4 + T cells during the primary, but not during the booster immunization. These data further support the notion that the regulation of capsular PSspecific IgG responses to intact bacteria is dependent on the nature of the subcapsular domain, and suggest a potential, general dichotomy between GP and GN bacteria.…”

“…Previous studies using intact heat-killed S. pneumoniae and a soluble pneumococcal conjugate vaccine strongly suggested that PS-specific IgG responses were derived from marginal zone and follicular B cells, respectively (18,19), with elicitation of distinct idiotypes on the PS-specific (serotype 14) IgG (17). Indeed, mice primed with intact serotype 14 S. pneumoniae do not elicit an augmented PS-specific IgG response following booster immunization with a soluble type 14 pneumococcal conjugate vaccine, in which the carrier protein is pneumococcal surface protein A (33), but do elicit an augmented response following booster immunization with intact GBS-III expressing type 14 PS (21).…”

“…For example, systemic immunization with intact S. pneumoniae induced PS-specific IgG that derived from splenic marginal zone B cells and expressed a distinct idiotype, whereas a pneumococcal conjugate vaccine of the same PS serotype (type 14) induced PS-specific IgG largely lacking this idiotype and derived from splenic follicular B cells (17)(18)(19).…”

Distinct Cellular Pathways for Induction of CD4+ T Cell–Dependent Antibody Responses to Antigen Expressed by Intact Bacteria Versus Isolated Soluble Antigen

“…This dichotomy was specifically dependent on whether the PS was coexpressed with protein in a particulate or soluble form (24). Of note, although alum adjuvant is particulate, Ag adsorbed to alum did not behave as a particulate Ag (22). In this regard, DCs exposed to alum-adsorbed Ag exhibited facilitated Ag uptake but did not internalize the alum particles (25).…”

“…We demonstrated previously that polysaccharide (PS)-and protein-specific IgG responses to intact extracellular bacteria (20), as well as soluble conjugate vaccines (21), are dependent on CD4 + T cells. However, the PS-specific IgG response to an intact bacterium arose from MZ B cells expressing a distinct and dominant idiotype, in contrast to the same PS-specific IgG response to a soluble conjugate vaccine, which arose from follicular B cells expressing a different idiotype(s) (21)(22)(23). This dichotomy was specifically dependent on whether the PS was coexpressed with protein in a particulate or soluble form (24).…”