title: 4-1BB (CD137) differentially regulates murine in vivo protein- and polysaccharide-specific immunoglobulin isotype responses to Streptococcus pneumoniae.
abstract: 4-1BB (CD137) is induced on activated CD4(+) and CD8(+) T cells and delivers a costimulatory signal upon binding the 4-1BB ligand (4-1BBL) expressed on antigen-presenting cells. Induction of 4-1BB is dependent on activation via the T-cell receptor (TCR) and possibly CD28. It was previously demonstrated that both an in vivo protein (pneumococcal surface protein A [PspA])- and polysaccharide (phosphorylcholine [PC] determinant of teichoic acid)-specific immunoglobulin (Ig) isotype response to Streptococcus pneumoniae was dependent on CD4(+) TCRalphabeta(+) T cells and B7-dependent costimulation through CD28. We thus postulated that 4-1BB costimulation would also play a role in regulating the in vivo anti-PspA and anti-PC response to S. pneumoniae. We demonstrate that mice genetically deficient in 4-1BBL elicit a markedly reduced IgM and IgG anti-PC but normal primary and secondary IgG anti-PspA responses to S. pneumoniae relative to those for wild-type mice. However, injection of an agonistic anti-4-1BB monoclonal antibody (MAb), while having no significant effect on the anti-PC response, strongly inhibits the primary anti-PspA response, the generation of PspA-specific memory, and germinal center formation but does not induce a lasting state of tolerance. In contrast, anti-4-1BB MAb has no effect on the anti-PspA response when injected only at the time of secondary immunization. Delay of the addition of anti-4-1BB leads to progressively less inhibition of the primary response up to day 8. This inhibition is independent of CD8(+) T cells and is associated with the expansion of CD4(+) T cells with an activated phenotype, which is partly dependent on B7-dependent costimulation. These data are the first to suggest a stimulatory role for endogenous 4-1BB-4-1BBL interactions during a humoral immune response to a pathogen and further underscore significant differences in costimulation requirements for an in vivo protein- versus polysaccharide-specific Ig isotype response to an extracellular bacterium.
authors.affiliation: Department of Pathology. Biomedical Instrumentation Center, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
authors.forename: Zheng-Qi
authors.initials: ZQ
authors.lastname: Wu
authors.forename: Abdul Q
authors.initials: AQ
authors.lastname: Khan
authors.forename: Yi
authors.initials: Y
authors.lastname: Shen
authors.forename: Karen M
authors.initials: KM
authors.lastname: Wolcott
authors.forename: Wojciech
authors.initials: W
authors.lastname: Dawicki
authors.forename: Tania H
authors.initials: TH
authors.lastname: Watts
authors.forename: Robert S
authors.initials: RS
authors.lastname: Mittler
authors.forename: Clifford M
authors.initials: CM
authors.lastname: Snapper
mesh_terms: D053330:4-1BB Ligand; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D015703:Antigens, CD; D001426:Bacterial Proteins / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation; D007114:Immunization; D007132:Immunoglobulin Isotypes / Q000097:blood*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D010767:Phosphorylcholine / Q000276:immunology; D022242:Pneumococcal Vaccines / Q000008:administration & dosage / Q000276:immunology; D011135:Polysaccharides, Bacterial / Q000737:chemistry / Q000276:immunology*; D017475:Receptors, Nerve Growth Factor / Q000276:immunology / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism*; D013296:Streptococcus pneumoniae / Q000276:immunology* / Q000472:pathogenicity; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053330:4-1BB Ligand; D000942:Antigens, Bacterial; D015703:Antigens, CD; D001426:Bacterial Proteins; D007132:Immunoglobulin Isotypes; D008024:Ligands; D022242:Pneumococcal Vaccines; D011135:Polysaccharides, Bacterial; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; C505975:Tnfsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha; C051592:pneumococcal surface protein A; D010767:Phosphorylcholine