LEF-1 and TCF-1 orchestrate T(FH) differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6

Nat Immunol. 2015 Sep;16(9):980-90. doi: 10.1038/ni.3226. Epub 2015 Jul 27.

Abstract

Follicular helper T cells (T(FH) cells) are specialized effector CD4(+) T cells that help B cells develop germinal centers (GCs) and memory. However, the transcription factors that regulate the differentiation of T(FH) cells remain incompletely understood. Here we report that selective loss of Lef1 or Tcf7 (which encode the transcription factor LEF-1 or TCF-1, respectively) resulted in T(FH) cell defects, while deletion of both Lef1 and Tcf7 severely impaired the differentiation of T(FH) cells and the formation of GCs. Forced expression of LEF-1 enhanced T(FH) differentiation. LEF-1 and TCF-1 coordinated such differentiation by two general mechanisms. First, they established the responsiveness of naive CD4(+) T cells to T(FH) cell signals. Second, they promoted early T(FH) differentiation via the multipronged approach of sustaining expression of the cytokine receptors IL-6Rα and gp130, enhancing expression of the costimulatory receptor ICOS and promoting expression of the transcriptional repressor Bcl6.

Publication types

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

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Cytokine Receptor gp130 / genetics
  • Cytokine Receptor gp130 / immunology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology*
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Germinal Center / immunology*
  • Germinal Center / metabolism
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-alpha / immunology*
  • Lymphoid Enhancer-Binding Factor 1 / genetics
  • Lymphoid Enhancer-Binding Factor 1 / immunology*
  • Mice
  • Proto-Oncogene Proteins c-bcl-6
  • Receptors, Interleukin-6 / genetics
  • Receptors, Interleukin-6 / immunology*
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism

Substances

  • Bcl6 protein, mouse
  • DNA-Binding Proteins
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Il6st protein, mouse
  • Lef1 protein, mouse
  • Lymphoid Enhancer-Binding Factor 1
  • Proto-Oncogene Proteins c-bcl-6
  • Receptors, Interleukin-6
  • Cytokine Receptor gp130