Both Innate Immunity and Type 1 Humoral Immunity toStreptococcus pneumoniaeAre Mediated by MyD88 but Differ in Their Relative Levels of Dependence on Toll-Like Receptor 2

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Abstract
Little is known regarding the role of Toll-like receptors (TLRs) in regulating protein- and polysaccharide-specific immunoglobulin (Ig) isotype production in response to an in vivo challenge with an extracellular bacterium. In this report we demonstrate that MyD88−/−, but not TLR2−/−, mice are markedly defective in their induction of multiple splenic proinflammatory cytokine- and chemokine-specific mRNAs after intraperitoneal (i.p.) challenge with heat-killedStreptococcus pneumoniaecapsular type 14 (S. pneumoniaetype 14). This is correlated with analogous responses in splenic cytokine protein release in vitro following addition ofS. pneumoniaetype 14. Consistent with these data, naïve MyD88−/−, but not TLR2−/−, mice are more sensitive to killing following i.p. challenge with liveS. pneumoniaetype 14, relative to responses in wild-type mice. However, prior immunization of MyD88−/−mice with heat-killedS. pneumoniaetype 14 protects against an otherwise-lethal challenge with liveS. pneumoniaetype 14. Surprisingly, both MyD88−/−and TLR2−/−mice exhibit striking and equivalent defects in elicitation of type 1 IgG isotypes (IgG3, IgG2b, and IgG2a), but not the type 2 IgG isotype, IgG1, specific for several protein and polysaccharide antigens, in response to i.p. challenge with heat-killedS. pneumoniaetype 14. Of note, the type 1 IgG isotype titers specific for pneumococcal surface protein A are reduced in MyD88−/−mice but not TLR2−/−mice. These data suggest that distinct TLRs may differentially regulate innate versus adaptive humoral immunity to intactS. pneumoniaeand are the first to implicate a role for TLR2 in shaping an in vivo type 1 IgG humoral immune response to a gram-positive extracellular bacterium.