Transmembrane activator, calcium modulator, and cyclophilin ligand interactor drives plasma cell differentiation in LPS-activated B cells

J Allergy Clin Immunol. 2009 Jun;123(6):1277-86.e5. doi: 10.1016/j.jaci.2009.03.019. Epub 2009 May 8.

Abstract

Background: Transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI) expression on B cells is upregulated by Toll-like receptor (TLR) 4.

Objective: We sought to examine whether TACI synergizes with TLR4 in driving immunoglobulin production by B cells and to examine the mechanism of this synergy.

Methods: Purified mouse naive B cells were stimulated with the TACI ligand a proliferation-inducing ligand (APRIL) and with suboptimal concentrations of the TLR4 ligand LPS in the presence or absence of IL-4. Immunoglobulin secretion was measured by means of ELISA. Surface IgG1-positive B cells and CD138+ plasmacytoid cells were enumerated by means of FACS. Expression of gamma1 and epsilon germline transcripts, activation-induced cytidine deaminase, and gamma1 and epsilon mature transcripts was measured by means of RT-PCR.

Results: APRIL synergized with LPS in driving B-cell proliferation and IgM, IgG1, IgG3, IgE, and IgA production. This was mediated by TACI because it was preserved in B-cell maturation antigen-/-, but not TACI-/-, B cells. APRIL and LPS synergized to promote isotype switching, as evidenced by increased expression of activation-induced cytidine deaminase and gamma1 and epsilon mature transcripts and generation of surface IgG1-positive cells. More importantly, APRIL and LPS strongly synergized to drive the plasma cell differentiation program, as evidenced by an increase in CD138+ cells and expression of B lymphocyte induced maturation protein-1 (Blimp-1), interferon regulatory factor-4 (IRF-4), and the spliced form of X-box binding protein-1 (XBP-1). TACI-/- mice had impaired IgM and IgG1 antibody responses to immunization, with a suboptimal dose of the type I T cell-independent antigen 2, 4, 6- Trinitrophenol (TNP)-LPS.

Conclusions: These observations suggest that TACI cooperates with TLR4 to drive B-cell differentiation and immunoglobulin production in vitro and in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Formation / immunology*
  • B-Cell Maturation Antigen / genetics
  • B-Cell Maturation Antigen / immunology
  • B-Cell Maturation Antigen / metabolism
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology*
  • Cell Proliferation / drug effects
  • Immunoglobulins / immunology
  • Immunoglobulins / metabolism
  • Interleukin-4 / pharmacology
  • Ligands
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / pharmacology
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Plasma Cells / drug effects
  • Plasma Cells / immunology*
  • Plasma Cells / metabolism
  • Toll-Like Receptor 4 / metabolism*
  • Transmembrane Activator and CAML Interactor Protein / genetics
  • Transmembrane Activator and CAML Interactor Protein / metabolism*
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / pharmacology*

Substances

  • B-Cell Maturation Antigen
  • Immunoglobulins
  • Ligands
  • Lipopolysaccharides
  • Tlr4 protein, mouse
  • Tnfrsf13b protein, mouse
  • Tnfsf13 protein, mouse
  • Toll-Like Receptor 4
  • Transmembrane Activator and CAML Interactor Protein
  • Tumor Necrosis Factor Ligand Superfamily Member 13
  • trinitrophenyl-lipopolysaccharide
  • Interleukin-4