ICOS maintains the T follicular helper cell phenotype by down-regulating Krüppel-like factor 2

J Exp Med. 2015 Feb 9;212(2):217-33. doi: 10.1084/jem.20141432. Epub 2015 Feb 2.

Abstract

The co-stimulators ICOS (inducible T cell co-stimulator) and CD28 are both important for T follicular helper (TFH) cells, yet their individual contributions are unclear. Here, we show that each molecule plays an exclusive role at different stages of TFH cell development. While CD28 regulated early expression of the master transcription factor Bcl-6, ICOS co-stimulation was essential to maintain the phenotype by regulating the novel TFH transcription factor Klf2 via Foxo1. Klf2 directly binds to Cxcr5, Ccr7, Psgl-1, and S1pr1, and low levels of Klf2 were essential to maintain this typical TFH homing receptor pattern. Blocking ICOS resulted in relocation of fully developed TFH cells back to the T cell zone and reversion of their phenotype to non-TFH effector cells, which ultimately resulted in breakdown of the germinal center response. Our study describes for the first time the exclusive role of ICOS and its downstream signaling in the maintenance of TFH cells by controlling their anatomical localization in the B cell follicle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD28 Antigens / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Down-Regulation
  • Female
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / metabolism
  • Gene Expression
  • Gene Expression Regulation*
  • Germinal Center / immunology
  • Germinal Center / metabolism
  • Humans
  • Inducible T-Cell Co-Stimulator Ligand / metabolism
  • Inducible T-Cell Co-Stimulator Protein / metabolism*
  • Kruppel-Like Transcription Factors / genetics*
  • Kruppel-Like Transcription Factors / metabolism*
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Knockout
  • Palatine Tonsil / immunology
  • Palatine Tonsil / metabolism
  • Phenotype*
  • Protein Binding
  • Receptors, CCR7 / metabolism
  • Receptors, CXCR5 / metabolism
  • Signal Transduction
  • T-Lymphocyte Subsets*
  • T-Lymphocytes, Helper-Inducer / cytology
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism*

Substances

  • CD28 Antigens
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Inducible T-Cell Co-Stimulator Ligand
  • Inducible T-Cell Co-Stimulator Protein
  • Klf2 protein, mouse
  • Kruppel-Like Transcription Factors
  • Membrane Glycoproteins
  • P-selectin ligand protein
  • Receptors, CCR7
  • Receptors, CXCR5