title: CD21/35 promotes protective immunity to Streptococcus pneumoniae through a complement-independent but CD19-dependent pathway that regulates PD-1 expression.
abstract: Humoral immunity to T cell-independent type 2 Ags (TI-2 Ag) is critical for protection against encapsulated bacteria such as Streptococcus pneumoniae. The CD21/35 receptor is thought to promote protective humoral immunity to encapsulated bacteria by enabling complement-decorated capsular polysaccharides to coligate the CD21/35-CD19 signaling complex with the B cell Ag receptor (BCR), thereby enhancing Ag-specific B cell activation. However, Ab responses to S. pneumoniae type 3 capsular polysaccharide (PPS-3) and other strong TI-2 Ags were significantly impaired in CD21/35(-/-) but not C3(-/-) or C4(-/-) mice. B cells from CD21/35(-/-) mice expressed significantly higher levels of cell surface CD19. CD21/35(-/-) B cells exhibited enhanced BCR-induced calcium responses and significantly higher expression of the inhibitory programmed death-1 (PD-1) receptor following immunization with a TI-2 Ag or BCR crosslinking. Reducing CD19 expression in CD21/35(-/-) mice normalized BCR-induced calcium responses, PD-1 induction, and PPS-3-specific IgG3 responses and restored protection during S. pneumoniae infection. PD-1 blockade also selectively rescued PPS-3-specific IgG3 responses in CD21/35(-/-) mice. Thereby, CD21/35 promotes protective humoral immunity to S. pneumoniae and other strong TI-2 Ags through a complement-independent pathway by negatively regulating CD19 expression and PD-1 induction.
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Haas
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Poe
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Tedder
mesh_terms: D000818:Animals; D000917:Antibody Formation; D000942:Antigens, Bacterial / Q000276:immunology; D018941:Antigens, CD19 / Q000235:genetics*; D000954:Antigens, Surface / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D003165:Complement System Proteins; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D011135:Polysaccharides, Bacterial / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D017463:Receptors, Complement 3b / Q000276:immunology*; D017464:Receptors, Complement 3d / Q000276:immunology*; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D018941:Antigens, CD19; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; C491383:Pdcd1 protein, mouse; D011135:Polysaccharides, Bacterial; D061026:Programmed Cell Death 1 Receptor; D011947:Receptors, Antigen, B-Cell; D017463:Receptors, Complement 3b; D017464:Receptors, Complement 3d; D003165:Complement System Proteins