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 Miyazaki1,8,
- Kazuko Miyazaki1,8,
- Shuwen Chen1,
- Vivek Chandra1,
- Keisuke Wagatsuma2,
- Yasutoshi Agata2,
- Hans-Reimer Rodewald3,
- Rintaro Saito4,
- Aaron N. Chang5,
- Nissi Varki6,
- Hiroshi Kawamoto7 and
- Cornelis Murre1
- 1Department of Molecular Biology, University of California at San Diego, La Jolla, California 92093, USA;
- 2Department of Biochemistry and Molecular Biology, Shiga University of Medical School, Shiga 520-2192, Japan;
- 3Division of Cellular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany;
- 4Department of Medicine, University of California at San Diego, La Jolla, California 92093, USA;
- 5Center for Computational Biology, Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA;
- 6Department of Pathology, University of California at San Diego, La Jolla, California 92093, USA;
- 7Department of Immunology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
- Corresponding author: murre{at}biomail.ucsd.edu
-
↵8 These authors contributed equally to this work.
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
Footnotes
-
Supplemental material is available for this article.
-
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.255331.114.
Freely available online through the Genes & Development Open Access option.
- Received November 4, 2014.
- Accepted January 8, 2015.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0.