Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility

Nature. 2013 Apr 25;496(7446):523-7. doi: 10.1038/nature12058.

Abstract

Germinal centres support antibody affinity maturation and memory formation. Follicular T-helper cells promote proliferation and differentiation of antigen-specific B cells inside the follicle. A genetic deficiency in the inducible co-stimulator (ICOS), a classic CD28 family co-stimulatory molecule highly expressed by follicular T-helper cells, causes profound germinal centre defects, leading to the view that ICOS specifically co-stimulates the follicular T-helper cell differentiation program. Here we show that ICOS directly controls follicular recruitment of activated T-helper cells in mice. This effect is independent from ICOS ligand (ICOSL)-mediated co-stimulation provided by antigen-presenting dendritic cells or cognate B cells, and does not rely on Bcl6-mediated programming as an intermediate step. Instead, it requires ICOSL expression by follicular bystander B cells, which do not present cognate antigen to T-helper cells but collectively form an ICOS-engaging field. Dynamic imaging reveals ICOS engagement drives coordinated pseudopod formation and promotes persistent T-cell migration at the border between the T-cell zone and the B-cell follicle in vivo. When follicular bystander B cells cannot express ICOSL, otherwise competent T-helper cells fail to develop into follicular T-helper cells normally, and fail to promote optimal germinal centre responses. These results demonstrate a co-stimulation-independent function of ICOS, uncover a key role for bystander B cells in promoting the development of follicular T-helper cells, and reveal unsuspected sophistication in dynamic T-cell positioning in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Bystander Effect / immunology*
  • Cell Movement*
  • DNA-Binding Proteins / metabolism
  • Genotype
  • Germinal Center / cytology*
  • Germinal Center / immunology
  • Inducible T-Cell Co-Stimulator Ligand / metabolism
  • Inducible T-Cell Co-Stimulator Protein / metabolism*
  • Lymphocyte Activation
  • Mice
  • Proto-Oncogene Proteins c-bcl-6
  • Pseudopodia / metabolism
  • Receptors, CXCR5
  • T-Lymphocytes, Helper-Inducer / cytology*
  • T-Lymphocytes, Helper-Inducer / immunology*

Substances

  • Bcl6 protein, mouse
  • CXCR5 protein, mouse
  • DNA-Binding Proteins
  • Icosl protein, mouse
  • Inducible T-Cell Co-Stimulator Ligand
  • Inducible T-Cell Co-Stimulator Protein
  • Proto-Oncogene Proteins c-bcl-6
  • Receptors, CXCR5