The Kinase mTORC1 Promotes the Generation and Suppressive Function of Follicular Regulatory T Cells

Immunity. 2017 Sep 19;47(3):538-551.e5. doi: 10.1016/j.immuni.2017.08.011.

Abstract

Follicular regulatory T (Tfr) cells differentiate from conventional regulatory T (Treg) cells and suppress excessive germinal center (GC) responses by acting on both GC B cells and T follicular helper (Tfh) cells. Here, we examined the impact of mTOR, a serine/threonine protein kinase that senses and integrates diverse environmental cues, on the differentiation and functional competency of Tfr cells in response to protein immunization or viral infection. By genetically deleting Rptor or Rictor, essential components for mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), respectively, we found that mTORC1 but not mTORC2 is essential for Tfr differentiation. Mechanistically, mTORC1-mediated phosphorylation of the transcription factor STAT3 induced the expression of the transcription factor TCF-1 by promoting STAT3 binding to the Tcf7 5'-regulatory region. Subsequently, TCF-1 bound to the Bcl6 promoter to induce Bcl6 expression, which launched the Tfr cell differentiation program. Thus, mTORC1 initiates Tfr cell differentiation by activating the TCF-1-Bcl-6 axis during immunization or infection.

Keywords: acute viral infection; follicular helper T cells; follicular regulatory T cells; mTORC1; protein immunization; regulatory T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Cell Differentiation / immunology
  • Cluster Analysis
  • Gene Expression Profiling
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • Immunization
  • Immunomodulation*
  • Immunophenotyping
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Transgenic
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Proto-Oncogene Proteins c-bcl-6 / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Biomarkers
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Multiprotein Complexes
  • Proto-Oncogene Proteins c-bcl-6
  • STAT3 Transcription Factor
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1