B cells in T follicular helper cell development and function: separable roles in delivery of ICOS ligand and antigen

J Immunol. 2014 Apr 1;192(7):3166-79. doi: 10.4049/jimmunol.1302617. Epub 2014 Mar 7.


B cells are required for follicular Th (Tfh) cell development, as is the ICOS ligand (ICOS-L); however, the separable contributions of Ag and ICOS-L delivery by cognate B cells to Tfh cell development and function are unknown. We find that Tfh cell and germinal center differentiation are dependent on cognate B cell display of ICOS-L, but only when Ag presentation by the latter is limiting, with the requirement for B cell expression of ICOS-L overcome by robust Ag delivery. These findings demonstrate that Ag-specific B cells provide different, yet compensatory, signals for Tfh cell differentiation, while reconciling conflicting data indicating a requirement for ICOS-L expression on cognate B cells for Tfh cell development with those demonstrating that the latter requirement could be bypassed in lieu of that tendered by noncognate B cells. Our findings clarify the separable roles of delivery of Ag and ICOS-L by cognate B cells for Tfh cell maturation and function, and have implications for using therapeutic ICOS blockade in settings of abundantly available Ag, such as in systemic autoimmunity.

Publication types

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

MeSH terms

  • Animals
  • Antigens / immunology*
  • Antigens, CD19 / genetics
  • Antigens, CD19 / immunology
  • Antigens, CD19 / metabolism
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Cell Proliferation
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Flow Cytometry
  • Inducible T-Cell Co-Stimulator Ligand / genetics
  • Inducible T-Cell Co-Stimulator Ligand / immunology*
  • Inducible T-Cell Co-Stimulator Ligand / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Microscopy, Confocal
  • Nitrophenols / immunology
  • Ovalbumin / immunology
  • Phenylacetates / immunology
  • Proto-Oncogene Proteins c-bcl-6
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism


  • Antigens
  • Antigens, CD19
  • Bcl6 protein, mouse
  • DNA-Binding Proteins
  • Icosl protein, mouse
  • Inducible T-Cell Co-Stimulator Ligand
  • Nitrophenols
  • Phenylacetates
  • Proto-Oncogene Proteins c-bcl-6
  • 4-hydroxy-5-nitrophenyl acetic acid
  • Ovalbumin