Haemophilus influenzae type b-outer membrane protein complex glycoconjugate vaccine induces cytokine production by engaging human toll-like receptor 2 (TLR2) and requires the presence of TLR2 for optimal immunogenicity
Department of Medicine, Division of Infectious Diseases and Immunology
Adaptor Proteins, Signal Transducing; Animals; Antibodies, Bacterial; Antigens, Differentiation; Bacterial Outer Membrane Proteins; Bone Marrow Cells; Carrier Proteins; Cell Line; Cells, Cultured; Cytokines; Dendritic Cells; Down-Regulation; Haemophilus Vaccines; Humans; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88; Neisseria meningitidis; Polysaccharides, Bacterial; Receptors, Cell Surface; Receptors, Immunologic; Toll-Like Receptor 2; Toll-Like Receptors; Tumor Necrosis Factor-alpha; Vaccines, Conjugate
Life Sciences | Medicine and Health Sciences
Conjugate vaccines consisting of the capsular polysaccharide (PS) of Haemophilus influenzae type b (Hib) covalently linked to carrier proteins, unlike pure PS, are immunogenic in infants and have significantly reduced Hib infections in the United States, but require multiple doses to induce protective anti-PS Ab titers. Hib-meningococcal outer membrane protein complex (OMPC) conjugate vaccine, however, elicits protective anti-PS Ab titers after one dose. We found that OMPC and Hib-OMPC engaged human Toll-like receptor 2 (TLR2) expressed in human embryonic kidney (HEK) cells, inducing IL-8 production, and engaged mouse TLR2 on bone marrow-derived dendritic cells, inducing TNF release. Hib conjugated to the carrier proteins CRM(197) and tetanus toxoid did not engage TLR2 on HEK or dendritic cells. Engagement of TLR2 by Hib-OMPC was MyD88 dependent, as Hib-OMPC-induced TNF production was ablated in MyD88 knockout (KO) mice. Hib-OMPC was significantly less immunogenic in TLR2 KO mice, inducing lower Hib PS IgG and IgM titers compared with those in wild-type mice. Splenocytes from OMPC-immunized TLR2 KO mice also produced significantly less IL-6 and TNF-alpha than those from wild-type mice. Hib-OMPC is unique among glycoconjugate vaccines by engaging TLR2, and the ability of Hib-OMPC to elicit protective levels of Abs after one dose may be related to TLR2-mediated induction and regulation of cytokines produced by T cells and macrophages in addition to the peptide/MHC II-dependent recruitment of T cell help commonly afforded by carrier proteins. TLR2 engagement by an adjuvant or carrier protein may be a useful strategy for augmentation of the anti-PS Ab response induced by glycoconjugate vaccines.
DOI of Published Version
J Immunol. 2004 Feb 15;172(4):2431-8.
Journal of immunology (Baltimore, Md. : 1950) outer membrane protein conjugate vaccine)
Latz, Eicke; Franko, Jennifer L.; Golenbock, Douglas; and Schreiber, John R., "Haemophilus influenzae type b-outer membrane protein complex glycoconjugate vaccine induces cytokine production by engaging human toll-like receptor 2 (TLR2) and requires the presence of TLR2 for optimal immunogenicity" (2004). Open Access Articles. 1106.