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The Lupus Susceptibility Gene Pbx1 Regulates the Balance between Follicular Helper T Cell and Regulatory T Cell Differentiation

Seung-Chul Choi, Tarun E. Hutchinson, Anton A. Titov, Howard R. Seay, Shiwu Li, Todd M. Brusko, Byron P. Croker, Shahram Salek-Ardakani and Laurence Morel
J Immunol July 15, 2016, 197 (2) 458-469; DOI: https://doi.org/10.4049/jimmunol.1502283
Seung-Chul Choi
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610
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Tarun E. Hutchinson
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610
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Anton A. Titov
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610
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Howard R. Seay
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610
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Shiwu Li
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610
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Todd M. Brusko
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610
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Byron P. Croker
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610
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Shahram Salek-Ardakani
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610
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Laurence Morel
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610
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Abstract

Pbx1 controls chromatin accessibility to a large number of genes and is entirely conserved between mice and humans. The Pbx1-d dominant-negative isoform is more frequent in CD4+ T cells from lupus patients than from healthy controls. Pbx1-d is associated with the production of autoreactive T cells in mice carrying the Sle1a1 lupus-susceptibility locus. Transgenic (Tg) expression of Pbx1-d in CD4+ T cells reproduced the phenotypes of Sle1a1 mice, with increased inflammatory functions of CD4+ T cells and impaired Foxp3+ regulatory T cell (Treg) homeostasis. Pbx1-d–Tg expression also expanded the number of follicular helper T cells (TFHs) in a cell-intrinsic and Ag-specific manner, which was enhanced in recall responses and resulted in Th1-biased Abs. Moreover, Pbx1-d–Tg CD4+ T cells upregulated the expression of miR-10a, miR-21, and miR-155, which were implicated in Treg and follicular helper T cell homeostasis. Our results suggest that Pbx1-d impacts lupus development by regulating effector T cell differentiation and promoting TFHs at the expense of Tregs. In addition, our results identify Pbx1 as a novel regulator of CD4+ T cell effector function.

Footnotes

  • This work was supported by National Institutes of Health Grants R01 AI045050 (to L.M.) and R01 AI087734 (to S.S.-A.).

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    ANA
    anti-nuclear Ab
    B6
    C57BL/6J
    B6.Foxpegfp
    B6.Foxp3-enhanced GFP
    B6.Ly5a
    B6.SJL-PtprcaPep3b/BoyJ
    BM
    bone marrow
    B6.OT-II
    B6.Cg-Tg(TcraTcrb)425Cbn/J
    B6.Rag-1−/−
    B6.129S7-Rag1tm1Mom/J
    B6.Sle1a1
    B6.Sle1a.1NZW/NZW
    GC
    germinal center
    iTreg
    induced Treg
    miRNA
    microRNA
    mLN
    mesenteric lymph node
    pTreg
    peripheral Treg
    RA
    retinoic acid
    SLE
    systemic lupus erythematosus
    TC
    B6.NZM-Sle1NZM2410/AegSle2NZM2410/AegSle3NZM2410/Aeg/LmoJ
    TD
    T dependent
    TEff
    effector T cell
    TEM
    effector memory T cell
    TFH
    follicular helper T cell
    TFR
    follicular regulatory T cell
    Tg
    transgene/transgenic
    TN
    naive T cell
    Treg
    Foxp3+ regulatory T cell
    tTreg
    thymic Treg.

  • Received October 26, 2015.
  • Accepted May 11, 2016.
  • Copyright © 2016 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 197 (2)
The Journal of Immunology
Vol. 197, Issue 2
15 Jul 2016
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The Lupus Susceptibility Gene Pbx1 Regulates the Balance between Follicular Helper T Cell and Regulatory T Cell Differentiation
Seung-Chul Choi, Tarun E. Hutchinson, Anton A. Titov, Howard R. Seay, Shiwu Li, Todd M. Brusko, Byron P. Croker, Shahram Salek-Ardakani, Laurence Morel
The Journal of Immunology July 15, 2016, 197 (2) 458-469; DOI: 10.4049/jimmunol.1502283

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The Lupus Susceptibility Gene Pbx1 Regulates the Balance between Follicular Helper T Cell and Regulatory T Cell Differentiation
Seung-Chul Choi, Tarun E. Hutchinson, Anton A. Titov, Howard R. Seay, Shiwu Li, Todd M. Brusko, Byron P. Croker, Shahram Salek-Ardakani, Laurence Morel
The Journal of Immunology July 15, 2016, 197 (2) 458-469; DOI: 10.4049/jimmunol.1502283
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