Toll-like receptor 7-induced naive human B-cell differentiation and immunoglobulin production

J Allergy Clin Immunol. 2009 Jan;123(1):224-230.e4. doi: 10.1016/j.jaci.2008.09.018. Epub 2008 Nov 7.

Abstract

Background: Toll-like receptors contribute to the establishment of adaptive immune responses.

Objective: The reported studies were conducted to examine the effects of the Toll-like receptor (TLR)-7 ligand, resiquimod, on human naive B-cell differentiation.

Methods: Naive human B cells were cultured with resiquimod in the presence or absence of IL-2 and IL-10. Secreted IgM and IgG were measured by ELISA, and IL-6, IL-10, and IFN-alpha were measured by a multiplex protein array. Cell proliferation was assessed by measuring [(3)H]thymidine uptake. mRNA for activation-induced cytidine deaminase and I(gamma 1)-C(mu) circle transcripts was measured by means of RT-PCR.

Results: Resiquimod induced the production of IgM and, to a lesser extent, IgG by naive human B cells in association with the secretion of IL-6 and IL-10, and a weak proliferative response. IL-2 and IL-10 synergized with resiquimod in markedly augmenting resiquimod-induced IgM and IgG production and proliferation. Resiquimod also stimulated production of IgG by B cells isolated from the blood of a patient with the X-linked hyper-IgM syndrome, with a greater response when these cells were costimulated with IL-2 and IL-10. The stimulated naive B cells from healthy volunteers displayed molecular evidence of immunoglobulin class-switch recombination-namely the appearance of activation-induced cytidine deaminase and I(gamma 1)-C(mu) circle transcripts.

Conclusion: Perturbation of TLR-7 on naive human B cells can lead to the induction of immunoglobulin class switch and IgG production in the absence of B-cell receptor cross-linking and CD40-CD40L interaction. The results are relevant to vaccine development and mechanisms by which microbial infection may lead to autoimmunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibody Formation / drug effects
  • Antibody Formation / genetics
  • Antibody Formation / immunology*
  • B-Lymphocytes / immunology*
  • CD40 Antigens / genetics
  • CD40 Antigens / immunology
  • CD40 Ligand / genetics
  • CD40 Ligand / immunology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Drug Synergism
  • Female
  • Gene Rearrangement, B-Lymphocyte / drug effects
  • Gene Rearrangement, B-Lymphocyte / genetics
  • Gene Rearrangement, B-Lymphocyte / immunology
  • Humans
  • Hyper-IgM Immunodeficiency Syndrome, Type 1 / genetics
  • Hyper-IgM Immunodeficiency Syndrome, Type 1 / immunology
  • Imidazoles / immunology
  • Imidazoles / pharmacology*
  • Immunoglobulin G / genetics
  • Immunoglobulin G / immunology*
  • Immunoglobulin M / genetics
  • Immunoglobulin M / immunology*
  • Interferon-alpha / genetics
  • Interferon-alpha / immunology
  • Interleukin-10 / immunology
  • Interleukin-10 / pharmacology
  • Interleukin-2 / immunology
  • Interleukin-2 / pharmacology
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • Ligands
  • Male
  • Middle Aged
  • Receptors, Antigen, B-Cell / genetics
  • Receptors, Antigen, B-Cell / immunology
  • Toll-Like Receptor 7 / agonists
  • Toll-Like Receptor 7 / genetics
  • Toll-Like Receptor 7 / immunology*

Substances

  • CD40 Antigens
  • IL10 protein, human
  • IL2 protein, human
  • IL6 protein, human
  • Imidazoles
  • Immunoglobulin G
  • Immunoglobulin M
  • Interferon-alpha
  • Interleukin-2
  • Interleukin-6
  • Ligands
  • Receptors, Antigen, B-Cell
  • TLR7 protein, human
  • Toll-Like Receptor 7
  • Interleukin-10
  • CD40 Ligand
  • resiquimod