Signals that influence T follicular helper cell differentiation and function

Semin Immunopathol. 2010 Jun;32(2):183-96. doi: 10.1007/s00281-009-0194-z. Epub 2010 Jan 27.


Follicular helper T cells have recently emerged as a separate CD4(+) T helper lineage specialised in provision of help to B cells. They develop independently from Th1, Th2 and Th17 cells and are critical for humoral immunity, including the generation of long-lived and high affinity plasma cells and memory cells crucial for long-term protection against infections. A stepwise differentiation programme has emerged in which T cell receptor (TCR) signalling strength, CD28-mediated costimulation, B cell-derived inducible costimulator ligand signals, induction of c-maf and actions of cytokines, including interleukin (IL)-6 and IL-21, lead to upregulation of the transcriptional repressor B cell lymphoma 6 (Bcl-6) that drives T follicular helper (Tfh) cell differentiation. Bcl-6 turns on a repression programme that targets Blimp-1, transcriptional regulators of other helper lineages and microRNAs. Their concerted actions modulate expression of chemokine receptors, surface molecules and cytokines critical for follicular homing and B cell helper functions. Here, we review the nature of Tfh cells providing help to B cells during the two phases of B cell activation that occur in the outer T zone and, for some B cells, in germinal centres (GC). Recent insights into the signalling events that drive terminal differentiation of Tfh cells critical for selecting somatically mutated GC B cells and the consequences of Tfh dysregulation for immunodeficiency and autoimmune pathology are discussed.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • Cell Differentiation / immunology*
  • Germinal Center / cytology
  • Germinal Center / immunology
  • Germinal Center / metabolism
  • Humans
  • Lymphocyte Activation / immunology
  • Signal Transduction / immunology*
  • T-Lymphocytes, Helper-Inducer / cytology*
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism