The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells

Nat Immunol. 2009 Feb;10(2):167-75. doi: 10.1038/ni.1690. Epub 2008 Dec 21.


The inducible costimulatory molecule ICOS has been suggested to be important in the development of interleukin 17 (IL-17)-producing helper T cells (T(H)-17 cells) and of follicular helper T cells (T(FH) cells). Here we show that ICOS-deficient mice had no defect in T(H)-17 differentiation but had fewer T(H)-17 cells after IL-23 stimulation and fewer T(FH) cells. We also show that T(FH) cells produced IL-17 and that T(FH) cells in ICOS-deficient mice were defective in IL-17 production. Both T(H)-17 and T(FH) cells had higher expression of the transcription factor c-Maf. Genetic loss of c-Maf resulted in a defect in IL-21 production and fewer T(H)-17 and T(FH) cells. Thus our data suggest that ICOS-induced c-Maf regulates IL-21 production that in turn regulates the expansion of T(H)-17 and T(FH) cells.

Publication types

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

MeSH terms

  • Animals
  • Antigens, Differentiation, T-Lymphocyte / genetics
  • Antigens, Differentiation, T-Lymphocyte / immunology
  • Antigens, Differentiation, T-Lymphocyte / metabolism*
  • Cell Differentiation / immunology
  • Cell Proliferation
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Gene Expression Regulation / immunology*
  • Inducible T-Cell Co-Stimulator Protein
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism
  • Interleukins / biosynthesis*
  • Interleukins / immunology
  • Mice
  • Mice, Transgenic
  • Oligonucleotide Array Sequence Analysis
  • Proto-Oncogene Proteins c-maf / biosynthesis*
  • Proto-Oncogene Proteins c-maf / immunology
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocyte Subsets / cytology*
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Helper-Inducer / cytology*
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Helper-Inducer / metabolism


  • Antigens, Differentiation, T-Lymphocyte
  • Icos protein, mouse
  • Inducible T-Cell Co-Stimulator Protein
  • Interleukin-17
  • Interleukins
  • Maf protein, mouse
  • Proto-Oncogene Proteins c-maf
  • interleukin-21