Induction of IgG3 to LPS via Toll-like receptor 4 co-stimulation

PLoS One. 2008;3(10):e3509. doi: 10.1371/journal.pone.0003509. Epub 2008 Oct 23.

Abstract

B-cells integrate antigen-specific signals transduced via the B-cell receptor (BCR) and antigen non-specific co-stimulatory signals provided by cytokines and CD40 ligation in order to produce IgG antibodies. Toll-like receptors (TLRs) also provide co-stimulation, but the requirement for TLRs to generate T-cell independent and T-cell dependent antigen specific antibody responses is debated. Little is known about the role of B-cell expressed TLRs in inducing antigen-specific antibodies to antigens that also activate TLR signaling. We found that mice lacking functional TLR4 or its adaptor molecule MyD88 harbored significantly less IgG3 natural antibodies to LPS, and required higher amounts of LPS to induce anti-LPS IgG3. In vitro, BCR and TLR4 signaling synergized, lowering the threshold for production of T-cell independent IgG3 and IL-10. Moreover, BCR and TLR4 directly associate through the transmembrane domain of TLR4. Thus, in vivo, BCR/TLR synergism could facilitate the induction of IgG3 antibodies against microbial antigens that engage both innate and adaptive B-cell receptors. Vaccines might exploit BCR/TLR synergism to rapidly induce antigen-specific antibodies before significant T-cell responses arise.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Formation / genetics
  • Cells, Cultured
  • Female
  • Humans
  • Immunoglobulin G / metabolism*
  • Lipopolysaccharides / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Myeloid Differentiation Factor 88 / physiology
  • Proto-Oncogene Proteins c-bcr / physiology
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism
  • Toll-Like Receptor 4 / physiology*
  • Up-Regulation / drug effects
  • Up-Regulation / genetics*
  • Up-Regulation / immunology*

Substances

  • Immunoglobulin G
  • Lipopolysaccharides
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Bcr protein, mouse
  • Proto-Oncogene Proteins c-bcr