MiR-23~27~24-mediated control of humoral immunity reveals a TOX-driven regulatory circuit in follicular helper T cell differentiation

Sci Adv. 2019 Dec 11;5(12):eaaw1715. doi: 10.1126/sciadv.aaw1715. eCollection 2019 Dec.


Follicular helper T (TFH) cells are essential for generating protective humoral immunity. To date, microRNAs (miRNAs) have emerged as important players in regulating TFH cell biology. Here, we show that loss of miR-23~27~24 clusters in T cells resulted in elevated TFH cell frequencies upon different immune challenges, whereas overexpression of this miRNA family led to reduced TFH cell responses. Mechanistically, miR-23~27~24 clusters coordinately control TFH cells through targeting a network of genes that are crucial for TFH cell biology. Among them, thymocyte selection-associated HMG-box protein (TOX) was identified as a central transcription regulator in TFH cell development. TOX is highly up-regulated in both mouse and human TFH cells in a BCL6-dependent manner. In turn, TOX promotes the expression of multiple molecules that play critical roles in TFH cell differentiation and function. Collectively, our results establish a key miRNA regulon that maintains optimal TFH cell responses for resultant humoral immunity.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation / genetics*
  • Gene Expression Regulation, Developmental / immunology
  • High Mobility Group Proteins / genetics
  • Humans
  • Immunity, Humoral / genetics*
  • Immunity, Humoral / immunology
  • Lymphocyte Activation / immunology
  • Mice
  • MicroRNAs / genetics
  • Proto-Oncogene Proteins c-bcl-6 / genetics
  • Signal Transduction
  • T-Lymphocytes / immunology*
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism


  • BCL6 protein, human
  • High Mobility Group Proteins
  • MicroRNAs
  • Mirn23b microRNA, mouse
  • Mirn24 microRNA, mouse
  • Mirn27 microRNA, mouse
  • Proto-Oncogene Proteins c-bcl-6
  • TOX protein, human