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Lack of Ikaros Deregulates Inflammatory Gene Programs in T Cells

Carolina Lyon de Ana, Ksenia Arakcheeva, Parul Agnihotri, Nicole Derosia and Susan Winandy
J Immunol February 15, 2019, 202 (4) 1112-1123; DOI: https://doi.org/10.4049/jimmunol.1801270
Carolina Lyon de Ana
Department of Pathology and Laboratory Medicine, Immunology Training Program, Boston University School of Medicine, Boston, MA 02118
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  • ORCID record for Carolina Lyon de Ana
Ksenia Arakcheeva
Department of Pathology and Laboratory Medicine, Immunology Training Program, Boston University School of Medicine, Boston, MA 02118
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Parul Agnihotri
Department of Pathology and Laboratory Medicine, Immunology Training Program, Boston University School of Medicine, Boston, MA 02118
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Nicole Derosia
Department of Pathology and Laboratory Medicine, Immunology Training Program, Boston University School of Medicine, Boston, MA 02118
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Susan Winandy
Department of Pathology and Laboratory Medicine, Immunology Training Program, Boston University School of Medicine, Boston, MA 02118
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Abstract

CD4 Th cells are organizers of the immune response, directing other immune cells to initiate and maintain effective humoral and cellular immunity. CD4 T cells differentiate into distinct Th effector or regulatory subsets in response to signals delivered to them during the course of infection. Ikaros is a transcription factor that is expressed in blood cells from the level of the hematopoietic stem cell. It is required for normal thymic T cell development and serves as a tumor suppressor, as lack of Ikaros in developing lymphoid cells results in leukemia. To study the role of Ikaros in CD4 T cell differentiation and function, an Ikaros conditional knockout mouse was developed such that Ikaros expression was deleted specifically in mature T cells, thus avoiding defects observed in germline Ikaros mutant mice. Using this model system, we have shown that in the absence of Ikaros, CD4 T cells are able to attain Th1, Th2, and Th17, but not inducible regulatory T, cell fates. However, they show enhanced expression of a cohort of proinflammatory cytokines, resulting in differentiation of Th17 cells with a phenotype that has been associated with autoimmunity and pathological inflammation. In addition, we define Ikaros as a repressor of the gene program associated with the response to type I IFNs, another key pathway whose deregulation is linked to autoimmunity. Taken together, these data definitively define Ikaros as a critical regulator at the center of the inflammatory response in T cells and highlight a potential role in suppressing autoimmunity.

This article is featured in In This Issue, p.1019

Footnotes

  • This work was supported by National Institutes of Health Grants AI113522 and AI133228 to S.W. P.A. was supported by an Immunology Training Program training grant funded by the National Institutes of Health (T32 A1007309).

  • The microarray data presented in this article have been submitted to the National Center for Biotechnology Information Expression Omnibus under accession number GSE119067.

  • Abbreviations used in this article:

    FDR
    false discovery rate
    GO
    gene ontology
    GSEA
    gene-set enrichment analysis
    HSC
    hematopoietic stem cell
    Ikflox
    Ikaros conditional knockout
    ISG
    IFN-stimulated gene
    iTreg
    inducible regulatory T
    KEGG
    Kyoto Encyclopedia of Genes and Genomes
    qRT-PCR
    quantitative real-time RT-PCR
    Treg
    regulatory T.

  • Received September 18, 2018.
  • Accepted December 10, 2018.
  • Copyright © 2019 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 202 (4)
The Journal of Immunology
Vol. 202, Issue 4
15 Feb 2019
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Lack of Ikaros Deregulates Inflammatory Gene Programs in T Cells
Carolina Lyon de Ana, Ksenia Arakcheeva, Parul Agnihotri, Nicole Derosia, Susan Winandy
The Journal of Immunology February 15, 2019, 202 (4) 1112-1123; DOI: 10.4049/jimmunol.1801270

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Lack of Ikaros Deregulates Inflammatory Gene Programs in T Cells
Carolina Lyon de Ana, Ksenia Arakcheeva, Parul Agnihotri, Nicole Derosia, Susan Winandy
The Journal of Immunology February 15, 2019, 202 (4) 1112-1123; DOI: 10.4049/jimmunol.1801270
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Print ISSN 0022-1767        Online ISSN 1550-6606