TLR4 signaling augments B lymphocyte migration and overcomes the restriction that limits access to germinal center dark zones

J Exp Med. 2009 Nov 23;206(12):2641-57. doi: 10.1084/jem.20091982. Epub 2009 Nov 16.

Abstract

B lymphocyte-intrinsic Toll-like receptor (TLR) signals amplify humoral immunity and can exacerbate autoimmune diseases. We identify a new mechanism by which TLR signals may contribute to autoimmunity and chronic inflammation. We show that TLR4 signaling enhances B lymphocyte trafficking into lymph nodes (LNs), induces B lymphocyte clustering and interactions within LN follicles, leads to sustained in vivo B cell proliferation, overcomes the restriction that limits the access of nonantigen-activated B cells to germinal center dark zones, and enhances the generation of memory and plasma cells. Intravital microscopy and in vivo tracking studies of B cells transferred to recipient mice revealed that TLR4-activated, but not nonstimulated, B cells accumulated within the dark zones of preexisting germinal centers even when transferred with antigen-specific B cells. The TLR4-activated cells persist much better than nonstimulated cells, expanding both within the memory and plasma cell compartments. TLR-mediated activation of B cells may help to feed and stabilize the spontaneous and ectopic germinal centers that are so commonly found in autoimmune individuals and that accompany chronic inflammation.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology
  • Autoimmunity / genetics
  • Autoimmunity / immunology
  • Cell Movement / genetics
  • Cell Movement / immunology*
  • Cell Proliferation
  • Chronic Disease
  • Germinal Center / immunology*
  • Immunologic Memory / genetics
  • Immunologic Memory / immunology
  • Inflammation / genetics
  • Inflammation / immunology
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Transgenic
  • Plasma Cells / immunology*
  • Signal Transduction / immunology*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology*

Substances

  • Tlr4 protein, mouse
  • Toll-Like Receptor 4