CD21/35 Promotes Protective Immunity to Streptococcus pneumoniae through a Complement-Independent but CD19-Dependent Pathway That Regulates PD-1 Expression

Abstract

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.

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