The E-Id protein axis modulates the activities of the PI3K-AKT-mTORC1-Hif1a and c-myc/p19Arf pathways to suppress innate variant TFH cell development, thymocyte expansion, and lymphomagenesis

Genes Dev. 2015 Feb 15;29(4):409-25. doi: 10.1101/gad.255331.114.

Abstract

It is now well established that the E and Id protein axis regulates multiple steps in lymphocyte development. However, it remains unknown how E and Id proteins mechanistically enforce and maintain the naïve T-cell fate. Here we show that Id2 and Id3 suppressed the development and expansion of innate variant follicular helper T (TFH) cells. Innate variant TFH cells required major histocompatibility complex (MHC) class I-like signaling and were associated with germinal center B cells. We found that Id2 and Id3 induced Foxo1 and Foxp1 expression to antagonize the activation of a TFH transcription signature. We show that Id2 and Id3 acted upstream of the Hif1a/Foxo/AKT/mTORC1 pathway as well as the c-myc/p19Arf module to control cellular expansion. We found that mice depleted for Id2 and Id3 expression developed colitis and αβ T-cell lymphomas. Lymphomas depleted for Id2 and Id3 expression displayed elevated levels of c-myc, whereas p19Arf abundance declined. Transcription signatures of Id2- and Id3-depleted lymphomas revealed similarities to genetic deficiencies associated with Burkitt lymphoma. We propose that, in response to antigen receptor and/or cytokine signaling, the E-Id protein axis modulates the activities of the PI3K-AKT-mTORC1-Hif1a and c-myc/p19Arf pathways to control cellular expansion and homeostatic proliferation.

Keywords: FOXO/mTORC1 pathway; Id proteins; T-cell lymphoma,; T-cell quiescence; c-Myc/p19Arf; tumor suppressor.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Cell Differentiation*
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Inhibitor of Differentiation Proteins / genetics
  • Inhibitor of Differentiation Proteins / metabolism*
  • Lymphoid Tissue / cytology
  • Lymphoma / physiopathology*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes / metabolism
  • Oncogene Protein v-akt / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism
  • STAT1 Transcription Factor
  • T-Lymphocytes, Helper-Inducer / cytology*
  • TOR Serine-Threonine Kinases / metabolism
  • Thymocytes / cytology*

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Inhibitor of Differentiation Proteins
  • Multiprotein Complexes
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • STAT1 Transcription Factor
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Oncogene Protein v-akt