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The Vitamin D Analog, TX527, Promotes a Human CD4+CD25highCD127low Regulatory T Cell Profile and Induces a Migratory Signature Specific for Homing to Sites of Inflammation

Femke Baeke, Hannelie Korf, Lut Overbergh, Annemieke Verstuyf, Lieven Thorrez, Leentje Van Lommel, Mark Waer, Frans Schuit, Conny Gysemans and Chantal Mathieu
J Immunol January 1, 2011, 186 (1) 132-142; DOI: https://doi.org/10.4049/jimmunol.1000695
Femke Baeke
*Laboratory of Experimental Medicine and Endocrinology,
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Hannelie Korf
*Laboratory of Experimental Medicine and Endocrinology,
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Lut Overbergh
*Laboratory of Experimental Medicine and Endocrinology,
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Annemieke Verstuyf
*Laboratory of Experimental Medicine and Endocrinology,
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Lieven Thorrez
†Gene Expression Unit, Department of Molecular Cell Biology, and
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Leentje Van Lommel
†Gene Expression Unit, Department of Molecular Cell Biology, and
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Mark Waer
‡Laboratory of Experimental Transplantation, Catholic University of Leuven, Leuven, Belgium
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Frans Schuit
†Gene Expression Unit, Department of Molecular Cell Biology, and
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Conny Gysemans
*Laboratory of Experimental Medicine and Endocrinology,
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Chantal Mathieu
*Laboratory of Experimental Medicine and Endocrinology,
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Abstract

The use of hypocalcemic vitamin D analogs is an appealing strategy to exploit the immunomodulatory actions of active vitamin D in vivo while circumventing its calcemic side effects. The functional modulation of dendritic cells by these molecules is regarded as the key mechanism underlying their ability to regulate T cell reactivity. In this article, we demonstrate the capacity of the vitamin D analog, TX527, to target T cells directly. Microarray analysis of purified human CD3+ T cells, cultured in the presence of TX527, revealed differential expression of genes involved in T cell activation, proliferation, differentiation, and migratory capacity. Accordingly, functional analysis showed a TX527-mediated suppression of the T cell proliferative capacity and activation status, accompanied by decreased expression of effector cytokines (IFN-γ, IL-4, and IL-17). Furthermore, TX527 triggered the emergence of CD4+CD25highCD127low regulatory T cells featuring elevated levels of IL-10, CTLA-4, and OX40 and the functional capacity to suppress activation and proliferation of effector T cells. Moreover, the vitamin D analog profoundly altered the homing receptor profile of T cells and their migration toward chemokine ligands. Remarkably, TX527 not only modulated skin-homing receptors as illustrated for the parent compound, but also reduced the expression of lymphoid organ-homing receptors (CD62L, CCR7, and CXCR4) and uniquely promoted surface expression of inflammatory homing receptors (CCR5, CXCR3, and CXCR6) on T cells. We conclude that TX527 directly affects human T cell function, thereby inhibiting effector T cell reactivity while inducing regulatory T cell characteristics, and imprints them with a specific homing signature favoring migration to sites of inflammation.

Footnotes

  • This work was supported by grants from the Flemish Research Foundation (Fonds Voor Wetenschappelijk Onderzoek Vlaanderen G.0552.06 and G.0649.08, a postdoctoral fellowship to C.G. and H.K., and a clinical fellowship to C.M.), the Belgium Program on Interuniversity Poles of Attraction initiated by the Belgian State (P5/17 and P6/40), the Katholieke Universiteit Leuven (GOA 2004/10, GOA 2009/10, and SymBioSys CoE EF/05/007), the 6th Framework Program of the European Union with SAVEBETA as well as of the 7th Framework Program of the European Union with Natural Immunomodulators as Novel Immunotherapies for Type 1 Diabetes, and the Juvenile Diabetes Research Foundation Center for β Cell Therapy in Diabetes (Grant 4-2005-1327).

  • The microarray data presented in this article have been submitted to the Gene Expression Omnibus under accession number GSE23984.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this paper:

    7-AAD
    7-aminoactinomycin D
    CLA
    cutaneous lymphocyte-associated Ag
    DC
    dendritic cell
    GADD45A
    growth arrest and DNA damage-inducible α
    GITR
    glucocorticoid-induced TNFR-related protein
    KEGG
    Kyoto Encyclopedia of Genes and Genomes
    ND
    not detected
    nTreg
    naturally occurring regulatory T cell
    1,25(OH)2D3
    1,25-dihydroxyvitamin D3
    Treg
    regulatory T cell
    VDR
    vitamin D receptor.

  • Received March 8, 2010.
  • Accepted October 31, 2010.
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The Journal of Immunology: 186 (1)
The Journal of Immunology
Vol. 186, Issue 1
1 Jan 2011
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The Vitamin D Analog, TX527, Promotes a Human CD4+CD25highCD127low Regulatory T Cell Profile and Induces a Migratory Signature Specific for Homing to Sites of Inflammation
Femke Baeke, Hannelie Korf, Lut Overbergh, Annemieke Verstuyf, Lieven Thorrez, Leentje Van Lommel, Mark Waer, Frans Schuit, Conny Gysemans, Chantal Mathieu
The Journal of Immunology January 1, 2011, 186 (1) 132-142; DOI: 10.4049/jimmunol.1000695

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The Vitamin D Analog, TX527, Promotes a Human CD4+CD25highCD127low Regulatory T Cell Profile and Induces a Migratory Signature Specific for Homing to Sites of Inflammation
Femke Baeke, Hannelie Korf, Lut Overbergh, Annemieke Verstuyf, Lieven Thorrez, Leentje Van Lommel, Mark Waer, Frans Schuit, Conny Gysemans, Chantal Mathieu
The Journal of Immunology January 1, 2011, 186 (1) 132-142; DOI: 10.4049/jimmunol.1000695
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