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* Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
Center for Vaccine Development, University of Maryland, Baltimore, MD 21201;
Laboratory of Genetics, National Cancer Institute, Bethesda, MD 20892;
University of Colorado Health Sciences Center, Denver, CO 80207; and
¶ Integrated Department of Immunology, National Jewish Medical and Research Center, Denver, CO 80207
IgG antipolysaccharide (PS) and antiprotein responses to Streptococcus pneumoniae (Pn) are both CD4+ T cell dependent. However, the primary IgG anti-PS response terminates more quickly, uses a shorter period of T cell help, fails to generate memory, and is more dependent on membrane Ig (mIg) signaling. We thus determined whether this limited anti-PS response to Pn reflected a greater propensity of PS-specific B cells to undergo apoptosis. We used mice that constitutively expressed the antiapoptotic protein Bcl-xL or Bcl-2 as a B cell-specific transgene. Both transgenic (Tg) mice exhibited increased absolute numbers of splenic B-1 and peritoneal B-1b and B-2 cells, subsets implicated in anti-PS responses, but not in marginal zone B (MZB) cells. Both Tg mouse strains elicited, in an apparently Fas-independent manner, a more prolonged and higher peak primary IgM and IgG anti-PS, but not antiprotein, response to Pn, but without PS-specific memory. A similar effect was not observed using purified PS or pneumococcal conjugate vaccine. In vitro, both splenic MZB and follicular Tg B cells synthesized DNA at markedly higher levels than their wild-type counterparts, following mIg cross-linking. This was associated with increased clonal expansion and decreased apoptosis. Using Lsc–/– mice, the Pn-induced IgG response specific for the capsular PS was found to be almost entirely dependent on MZB cells. Collectively, these data suggest that apoptosis may limit mIg-dependent clonal expansion of PS-specific B cells during a primary immune response to an intact bacterium, as well as decrease the pool of PS-responding B cell subsets.
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 Opinions and assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Department of Defense or the Uniformed Services University of the Health Sciences.
2 This study was supported by National Institutes of Health Grants 1R01 AI49192 and the Uniformed Services University of the Health Sciences Dean’s Research and Education Endowment Fund.
3 G.C. and A.Q.K. share first authorship equally.
4 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
5 Abbreviations used in this paper: PS, polysaccharide; WT, wild type; TI, T cell independent; TD, T cell dependent; Pn, Streptococcus pneumoniae; mIg, membrane Ig; Btk, Bruton’s tyrosine kinase; GC, germinal center; Tg, transgenic; Pn14, Pn capsular type 14; PspA, pneumococcal surface protein A; PPS14, purified pneumococcal capsular polysaccharide, type 14; 
-dex, dextran-conjugated anti-IgD Ab; KLH, keyhole limpet hemocyanin; ODN, oligodeoxynucleotide; PI, proliferation index; MZB, marginal zone B; FB, follicular B; PC, phosphorylcholine; C-AFC, Ab-forming cell.
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