A fundamental role for interleukin-21 in the generation of T follicular helper cells

Immunity. 2008 Jul 18;29(1):127-37. doi: 10.1016/j.immuni.2008.06.001. Epub 2008 Jul 3.

Abstract

T cell help to B cells is a fundamental property of adaptive immunity, yet only recently have many of the cellular and molecular mechanisms of T cell help emerged. T follicular helper (Tfh) cells are the CD4(+) T helper cells that provide cognate help to B cells for high-affinity antibody production in germinal centers (GC). Tfh cells produce interleukin-21 (IL-21), and we show that IL-21 was necessary for GC formation. However, the central role of IL-21 in GC formation reflected its effects on Tfh cell generation rather than on B cells. Expression of the inducible costimulator (ICOS) was necessary for optimal production of IL-21, indicative of interplay between these two Tfh cell-expressed molecules. Finally, we demonstrate that IL-21's costimulatory capacity for T helper cell differentiation operated at the level of the T cell receptor signalosome through Vav1, a signaling molecule that controls T cell helper function. This study reveals a previously unappreciated role for Tfh cells in the formation of the GC and isotype switching through a CD4(+) T cell-intrinsic requirement for IL-21.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Differentiation, T-Lymphocyte / immunology
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology
  • Blotting, Western
  • Cell Differentiation / immunology
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Germinal Center / cytology*
  • Germinal Center / immunology
  • Immunoglobulin Class Switching / immunology
  • Immunohistochemistry
  • Inducible T-Cell Co-Stimulator Protein
  • Interleukins / immunology*
  • Interleukins / metabolism
  • Lymphocyte Activation / immunology
  • Lymphocyte Cooperation / immunology*
  • Mice
  • Microscopy, Confocal
  • Proto-Oncogene Proteins c-vav / immunology
  • Proto-Oncogene Proteins c-vav / metabolism
  • T-Lymphocyte Subsets / cytology*
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocytes, Helper-Inducer / cytology*
  • T-Lymphocytes, Helper-Inducer / immunology
  • Transfection

Substances

  • Antigens, Differentiation, T-Lymphocyte
  • Icos protein, mouse
  • Inducible T-Cell Co-Stimulator Protein
  • Interleukins
  • Proto-Oncogene Proteins c-vav
  • Vav1 protein, mouse
  • interleukin-21

Associated data

  • GEO/GSE3982