title: 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.
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.
authors.affiliation: Department of Molecular Biology, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Masaki
authors.initials: M
authors.lastname: Miyazaki
authors.affiliation: Department of Molecular Biology, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Kazuko
authors.initials: K
authors.lastname: Miyazaki
authors.affiliation: Department of Molecular Biology, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Shuwen
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Molecular Biology, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Vivek
authors.initials: V
authors.lastname: Chandra
authors.affiliation: Department of Biochemistry and Molecular Biology, Shiga University of Medical School, Shiga 520-2192, Japan;
authors.forename: Keisuke
authors.initials: K
authors.lastname: Wagatsuma
authors.affiliation: Department of Biochemistry and Molecular Biology, Shiga University of Medical School, Shiga 520-2192, Japan;
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Agata
authors.affiliation: Division of Cellular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany;
authors.forename: Hans-Reimer
authors.initials: HR
authors.lastname: Rodewald
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Rintaro
authors.initials: R
authors.lastname: Saito
authors.affiliation: Center for Computational Biology, Institute for Genomic Medicine, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Chang
authors.affiliation: Department of Pathology, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Nissi
authors.initials: N
authors.lastname: Varki
authors.affiliation: Department of Immunology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawamoto
authors.affiliation: Department of Molecular Biology, University of California at San Diego, La Jolla, California 92093, USA; murre@biomail.ucsd.edu.
authors.forename: Cornelis
authors.initials: C
authors.lastname: Murre
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000378:metabolism*; D008221:Lymphoid Tissue / Q000166:cytology; D008223:Lymphoma / Q000503:physiopathology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D050794:STAT1 Transcription Factor; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D060168:Thymocytes / Q000166:cytology*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D019941:Cyclin-Dependent Kinase Inhibitor p16; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051796:Inhibitor of Differentiation Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D016271:Proto-Oncogene Proteins c-myc; D050794:STAT1 Transcription Factor; D058570:TOR Serine-Threonine Kinases; C417743:Cdkn2a protein, mouse; C489428:Myc protein, mouse
keywords: FOXO/mTORC1 pathway; Id proteins; T-cell lymphoma,; T-cell quiescence; c-Myc/p19Arf; tumor suppressor