title: A novel ICOS-independent, but CD28- and SAP-dependent, pathway of T cell-dependent, polysaccharide-specific humoral immunity in response to intact Streptococcus pneumoniae versus pneumococcal conjugate vaccine.
abstract: 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.
authors.affiliation: Department of Pathology, Uniformed Services University of the Health Sciences, National Institutes of Health, Bethesda, MD 20814, USA.
authors.forename: Quanyi
authors.initials: Q
authors.lastname: Chen
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Cannons
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
authors.forename: Hisaya
authors.initials: H
authors.lastname: Akiba
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Schwartzberg
authors.forename: Clifford M
authors.initials: CM
authors.lastname: Snapper
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000502:physiology*; D016667:Bacterial Capsules / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D001426:Bacterial Proteins / Q000276:immunology / Q000378:metabolism; D001666:Binding Sites, Antibody; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D005260:Female; D060889:Inducible T-Cell Co-Stimulator Protein; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010767:Phosphorylcholine / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D022541:Streptococcal Vaccines / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000276:immunology*; D018074:Vaccines, Conjugate / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism
chemical_list: D000907:Antibodies, Bacterial; D000945:Antigens, Differentiation, T-Lymphocyte; D001426:Bacterial Proteins; D018106:CD28 Antigens; D018984:Epitopes, T-Lymphocyte; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D047908:Intracellular Signaling Peptides and Proteins; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; C110344:SpsA protein, Streptococcus pneumoniae; D022541:Streptococcal Vaccines; D018074:Vaccines, Conjugate; C056696:pneumococcal polysaccharide, type 14; D010767:Phosphorylcholine