Faculty Collaboration Database

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. J Immunol 2004 Feb 15;172(4):2431-8

Date

02/07/2004

Pubmed ID

14764714

DOI

10.4049/jimmunol.172.4.2431

Scopus ID

2-s2.0-0842300354 (requires institutional sign-in at Scopus site)   118 Citations

Abstract

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.

Author List

Latz E, Franko J, Golenbock DT, Schreiber JR

MESH terms used to index this publication - Major topics in bold

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