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

Masaki Miyazaki, Kazuko Miyazaki, Shuwen Chen, Vivek Chandra, Keisuke Wagatsuma, Yasutoshi Agata, Hans Reimer Rodewald, Rintaro Saito, Aaron N. Chang, Nissi Varki, Hiroshi Kawamoto, Cornelis Murre

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

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 ab 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.

Original languageEnglish
Pages (from-to)409-425
Number of pages17
JournalGenes and Development
Volume29
Issue number4
DOIs
Publication statusPublished - 2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

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