The transcription factor KLF2 restrains CD4⁺ T follicular helper cell differentiation

Immunity. 2015 Feb 17;42(2):252-264. doi: 10.1016/j.immuni.2015.01.013.

Abstract

T follicular helper (Tfh) cells are essential for efficient B cell responses, yet the factors that regulate differentiation of this CD4(+) T cell subset are incompletely understood. Here we found that the KLF2 transcription factor serves to restrain Tfh cell generation. Induced KLF2 deficiency in activated CD4(+) T cells led to increased Tfh cell generation and B cell priming, whereas KLF2 overexpression prevented Tfh cell production. KLF2 promotes expression of the trafficking receptor S1PR1, and S1PR1 downregulation is essential for efficient Tfh cell production. However, KLF2 also induced expression of the transcription factor Blimp-1, which repressed transcription factor Bcl-6 and thereby impaired Tfh cell differentiation. Furthermore, KLF2 induced expression of the transcription factors T-bet and GATA3 and enhanced Th1 differentiation. Hence, our data indicate KLF2 is pivotal for coordinating CD4(+) T cell differentiation through two distinct and complementary mechanisms: via control of T cell localization and by regulation of lineage-defining transcription factors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigens, CD / biosynthesis
  • Antigens, Differentiation, T-Lymphocyte / biosynthesis
  • B-Lymphocytes / immunology
  • Cell Differentiation / immunology*
  • DNA-Binding Proteins / biosynthesis
  • Down-Regulation
  • GATA3 Transcription Factor / biosynthesis
  • Gene Knockout Techniques
  • Kruppel-Like Transcription Factors / biosynthesis
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / immunology*
  • Lectins, C-Type / biosynthesis
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Positive Regulatory Domain I-Binding Factor 1
  • Proto-Oncogene Proteins c-bcl-6
  • Receptors, Lysosphingolipid / biosynthesis
  • Receptors, Lysosphingolipid / metabolism
  • Sphingosine-1-Phosphate Receptors
  • T-Box Domain Proteins / biosynthesis
  • Th1 Cells / cytology*
  • Th1 Cells / immunology*
  • Transcription Factors / biosynthesis
  • Transcription Factors / metabolism

Substances

  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • Bcl6 protein, mouse
  • CD69 antigen
  • DNA-Binding Proteins
  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • Klf2 protein, mouse
  • Kruppel-Like Transcription Factors
  • Lectins, C-Type
  • Prdm1 protein, mouse
  • Proto-Oncogene Proteins c-bcl-6
  • Receptors, Lysosphingolipid
  • S1pr1 protein, mouse
  • Sphingosine-1-Phosphate Receptors
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Transcription Factors
  • Positive Regulatory Domain I-Binding Factor 1