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* Department of Pathology, Uniformed Services University of the Health Sciences, and
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20814;
School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia; and
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
Polysaccharide (PS)- and protein-specific murine IgG responses to intact Streptococcus pneumoniae (Pn) are both dependent on CD4+ T cell help, B7-dependent costimulation, and CD40/CD40 ligand interactions. However, the primary PS-specific, relative to protein-specific, IgG response terminates more rapidly, requires a shorter period of T cell help and B7-dependent costimulation, and fails to generate memory. In light of the critical role for ICOS/ICOS ligand interactions in sustaining T cell-dependent Ig responses and promoting germinal center reactions, we hypothesized that this interaction was nonessential for PS-specific IgG responses to Pn. We now demonstrate that ICOS–/–, relative to wild-type, mice elicit a normal PS-specific IgG isotype response to Pn, despite marked inhibition of both the primary and secondary IgG anti-protein (i.e., PspA, PspC, and PsaA) response. A blocking anti-ICOS ligand mAb injected during primary Pn immunization inhibits both the primary anti-protein response and the generation of protein-specific memory, but has no effect when injected during secondary immunization. In contrast to Pn, both PS- and protein-specific IgG responses to a pneumococcal conjugate vaccine are inhibited in ICOS–/– mice. ICOS–/– mice immunized with intact Pn or conjugate exhibit nearly complete abrogation in germinal center formation. Finally, although mice that lack the adaptor molecule SAP (SLAM-associated protein) resemble ICOS–/– mice (and can exhibit decreased ICOS expression), we observe that the PS-specific, as well as protein-specific, IgG responses to both Pn and conjugate are markedly defective in SAP–/– mice. These data define a novel T cell-, SAP-, and B7-dependent, but ICOS-independent, extrafollicular pathway of Ig induction.
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 Grants 1R01 AI49192 (to C.M.S.) and the Uniformed Services University of the Health Sciences Dean’s Research and Education Endowment Fund (to C.M.S.) and by funding from the intramural program of the National Human Genome Research Institute (to P.L.S.).
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 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: Pn14, intact Streptococcus pneumoniae, capsular type 14; CpG-ODN, CpG-containing oligodeoxynucleotide; FB, follicular B; GC, germinal center; ICOSL, ICOS ligand; KLH, keyhole limpet hemocyanin; MZB, marginal zone B; NP, (4-hydroxy-3-nitrophenyl)acetyl; PC, phosphorylcholine determinant of teichoic or lipoteichoic acid; Pn, intact Streptococcus pneumoniae; PPS14, capsular polysaccharide, serotype 14; PS, polysaccharide; PsaA, pneumococcal surface adhesin A; PspA, pneumococcal surface protein A; PspC, pneumococcal surface protein C; SAP, SLAM-associated protein; TD, T cell dependent; TI, T cell independent; WT, wild type.
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