title: Endogenous IL-1R1 signaling is critical for cognate CD4+ T cell help for induction of in vivo type 1 and type 2 antipolysaccharide and antiprotein Ig isotype responses to intact Streptococcus pneumoniae, but not to a soluble pneumococcal conjugate vaccine.
abstract: 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-gamma, IL-5, or IL-13 secretion upon restimulation with Pn in vitro, whereas MyD88(-/-) mice secreted normal levels of IFN-gamma 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.
authors.affiliation: Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
authors.forename: Quanyi
authors.initials: Q
authors.lastname: Chen
authors.forename: Goutam
authors.initials: G
authors.lastname: Sen
authors.forename: Clifford M
authors.initials: CM
authors.lastname: Snapper
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000235:genetics; D001426:Bacterial Proteins / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D011008:Pneumococcal Infections / Q000517:prevention & control*; D022242:Pneumococcal Vaccines / Q000276:immunology; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D022541:Streptococcal Vaccines / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D018074:Vaccines, Conjugate / Q000276:immunology
chemical_list: D001426:Bacterial Proteins; D016207:Cytokines; D007074:Immunoglobulin G; D022242:Pneumococcal Vaccines; D053573:Receptors, Interleukin-1 Type I; D022541:Streptococcal Vaccines; D018074:Vaccines, Conjugate; C051592:pneumococcal surface protein A