Linterman, MichelleGarcia De Vinuesa, Maria Carola2015-12-101863-2297http://hdl.handle.net/1885/64100Follicular 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.Keywords: B lymphocyte induced maturation protein 1; B7 antigen; CD134 antigen; CD150 antigen; CD28 antigen; CD30 antigen; CD4 antigen; CD86 antigen; chemokine; chemokine receptor CCR7; chemokine receptor CXCR5; cytokine; Fas antigen; interleukin 21; interleukin 21 Bcl-6; CD28; Costimulation; ICOS; IL-21; SAP (Sh2d1a); T follicular helper cells (Tfh); TCR signalling201010.1007/s00281-009-0194-z2016-02-24