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

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

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  • 1Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
  • 21] Department of Microbiology, University of Iowa, Iowa City, Iowa, USA. [2] Interdisciplinary Immunology Graduate Program, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
  • 3Department of Microbiology, University of Iowa, Iowa City, Iowa, USA.
  • 4Department of Physics, The George Washington University, Washington, DC, USA.
  • 5Section on Cellular and Developmental Biology, NICHD, NIH, Bethesda, Maryland, USA.


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.

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