Antipolysaccharide and Antiprotein Ig Isotype Responses to Intact Streptococcus pneumoniae, but Not to a Soluble

MyD88/ mice exhibit defective innate, diminished CD4 T cell-dependent (TD) type 1, but enhanced type 2, humoral immunity in response to intact Streptococcus pneumoniae (Pn). Because type 1 IL-1R (IL-1R1) signaling is MyD88 dependent, a role for endogenous IL-1 was determined. IL-1R1/, in contrast to MyD88/, mice exhibited relatively intact innate splenic cytokine expression in response to Pn. Nevertheless, IL-1R1/, like MyD88/, mice were more sensitive to killing with live Pn relative to wild-type controls. Although IL-1R1/ mice elicited a normal T cell-independent IgM antipolysaccharide (PS) response to heat-killed Pn, the induction of PS- and protein-specific cognate, but not noncognate, TD type 1 and type 2 IgG isotypes were markedly reduced. Additionally, CD4 T cells from Pn-primed IL-1R1/ mice failed to elicit IFN-, IL-5, or IL-13 secretion upon restimulation with Pn in vitro, whereas MyD88/ mice secreted normal levels of IFN- and enhanced levels of IL-5 and IL-13. In contrast, IgG responses to a soluble, pneumococcal protein-PS conjugate, with or without adjuvant, showed little dependence on IL-1R1 and normal CD4 T cell priming. These data are the first to demonstrate a nonredundant role for endogenous IL-1 in TD induction of humoral immune responses to an intact pathogen, although not a pathogen-derived soluble conjugate, suggesting that antigenic context is a key determinant for IL-1 dependence. These data further suggest that IL-1 may be critical for preserving CD4 Th2 function in the presence, but not absence, of MyD88-dependent signaling via TLRs. The Journal of Immunology, 2006, 177: 6044–6051. I interleukin-1 and IL-1 are proinflammatory cytokines thatexert largely overlapping biological effects, both inducingcell signaling exclusively through IL-1R1 (1). Soluble IL-1R antagonist also binds to IL-1R1 but does not exert agonistic ac