Differential Idiotype Utilization for the In Vivo Type 14 Capsular Polysaccharide-Specific Ig Responses to Intact Streptococcus pneumoniae versus a Pneumococcal Conjugate Vaccine

Abstract

Murine IgG responses specific for the capsular polysaccharide (pneumococcal capsular polysaccharide serotype 14; PPS14) of Streptococcus pneumoniae type 14 (Pn14), induced in response to intact Pn14 or a PPS14–protein conjugate, are both dependent on CD4+ T cell help but appear to use marginal zone versus follicular B cells, respectively. In this study, we identify an idiotype (44.1-Id) that dominates the PPS14-specific IgG, but not IgM, responses to intact Pn14, isolated PPS14, and Group B Streptococcus (strain COH1-11) expressing capsular polysaccharide structurally identical to PPS14. The 44.1-Id, however, is not expressed in the repertoire of natural PPS14-specific Abs. In distinct contrast, PPS14-specific IgG responses to a soluble PPS14–protein conjugate exhibit minimal usage of the 44.1-Id, although significant 44.1-Id expression is elicited in response to conjugate attached to particles. The 44.1-Id elicited in response to intact Pn14 was expressed in similar proportions among all four IgG subclasses during both the primary and secondary responses. The 44.1-Id usage was linked to the Igha, but not Ighb, allotype and was associated with induction of relatively high total PPS14-specific IgG responses. In contrast to PPS14–protein conjugate, avidity maturation of the 44.1-Id–dominant PPS14-specific IgG responses was limited, even during the highly boosted T cell-dependent PPS14-specific secondary responses to COH1-11. These results indicate that different antigenic forms of the same capsular polysaccharide can recruit distinct B cell clones expressing characteristic idiotypes under genetic control and suggest that the 44.1-Id is derived from marginal zone B cells.

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

“…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).…”

“…In this regard, we demonstrated previously that anti-PPS14 IgG elicited in response to a covalent conjugate of PPS14 and protein presented on the surface of 1-mm latex particles exhibits a distinct idiotype (44.1-Id) (23,24) that is secreted by MZ B cells (21,22), whereas the soluble conjugate fails to elicit 44.1-Id and instead induces an anti-PPS14 IgG response from follicular B cells. The potential relationship between these latter observations and the use of distinct APCs to induce CD4 + T cell activation in response to these different forms of Ag remains to be determined.…”