T-B-cell entanglement and ICOSL-driven feed-forward regulation of germinal centre reaction

Nature. 2015 Jan 8;517(7533):214-8. doi: 10.1038/nature13803. Epub 2014 Oct 15.


The germinal centre (GC) reaction supports affinity-based B-cell competition and generates high-affinity bone-marrow plasma cells (BMPCs). How follicular T-helper (TFH) cells regulate GC selection is not clear. Using competitive mixed chimaera, we show here that, beyond the role in promoting TFH development, ICOSL (inducible T-cell co-stimulator ligand, also known as ICOSLG) is important for individual B cells to competitively participate in the GC reaction and to develop into BMPCs. Using intravital imaging aided by a calcium reporter, we further show that ICOSL promotes an 'entangled' mode of TFH-B-cell interactions, characterized by brief but extensive surface engagement, productive T-cell calcium spikes, and B-cell acquisition of CD40 signals. Reiterated entanglement promotes outer-zone co-localization of outcompeting GC B cells together with TFH cells, affording the former increased access to T-cell help. ICOSL on GC B cells is upregulated by CD40 signals. Such an intercellular positive feedback between contact-dependent help and ICOSL-controlled entanglement promotes positive selection and BMPC development, as evidenced by observations that higher-affinity B-cell receptor variants are enriched in the ICOSL(high) fraction, that numerically disadvantaged ICOSL-deficient GC B cells or BMPCs exhibit strong affinity compensation in competitive chimaera, and that when GC competition proceeds without ICOSL, selection of high-affinity variants in otherwise normal GC reactions is impaired. By demonstrating entanglement as the basic form of GC TFH-B-cell interactions, identifying ICOSL as a molecular linkage between T-B interactional dynamics and positive selection for high-affinity BMPC formation, our study reveals a pathway by which TFH cells control the quality of long-lived humoral immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / immunology
  • Antibodies / metabolism
  • Antibody Formation
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / immunology
  • Feedback
  • Germinal Center / cytology*
  • Germinal Center / immunology*
  • Inducible T-Cell Co-Stimulator Ligand / immunology
  • Inducible T-Cell Co-Stimulator Ligand / metabolism*
  • Mice
  • Plasma Cells / cytology
  • Plasma Cells / immunology
  • Plasma Cells / metabolism
  • Signal Transduction / immunology
  • T-Lymphocytes, Helper-Inducer / cytology*
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism


  • Antibodies
  • Icosl protein, mouse
  • Inducible T-Cell Co-Stimulator Ligand