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

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.

Author information

1
Department of Molecular Biology, University of California at San Diego, La Jolla, California 92093, USA;
2
Department of Biochemistry and Molecular Biology, Shiga University of Medical School, Shiga 520-2192, Japan;
3
Division of Cellular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany;
4
Department of Medicine, University of California at San Diego, La Jolla, California 92093, USA;
5
Center for Computational Biology, Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA;
6
Department of Pathology, University of California at San Diego, La Jolla, California 92093, USA;
7
Department of Immunology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
8
Department of Molecular Biology, University of California at San Diego, La Jolla, California 92093, USA; murre@biomail.ucsd.edu.

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

PMID:
25691468
PMCID:
PMC4335296
DOI:
10.1101/gad.255331.114
[Indexed for MEDLINE]
Free PMC Article

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