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.
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(+)CD25(high)CD127(low) 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.
Laboratory of Experimental Medicine and Endocrinology, Catholic University of Leuven, Leuven, Belgium.
Femke
F
Baeke
Hannelie
H
Korf
Lut
L
Overbergh
Annemieke
A
Verstuyf
Lieven
L
Thorrez
Leentje
L
Van Lommel
Mark
M
Waer
Frans
F
Schuit
Conny
C
Gysemans
Chantal
C
Mathieu
D000480:Alkynes; D017252:CD3 Complex / Q000096:biosynthesis / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000502:physiology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006131:Growth Inhibitors / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis*; D053699:Interleukin-7 Receptor alpha Subunit / Q000096:biosynthesis* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D054447:Receptors, CCR10 / Q000096:biosynthesis; D054398:Receptors, CCR4 / Q000096:biosynthesis; D019713:Receptors, CCR5 / Q000096:biosynthesis; D054367:Receptors, CXCR3 / Q000096:biosynthesis; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000096:biosynthesis; D011991:Receptors, Virus / Q000096:biosynthesis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D014158:Transcription, Genetic / Q000276:immunology
D000480:Alkynes; C515706:CCR10 protein, human; C515354:CCR4 protein, human; D017252:CD3 Complex; C515187:CXCR3 protein, human; C106330:CXCR6 protein, human; D018984:Epitopes, T-Lymphocyte; D006131:Growth Inhibitors; D018836:Inflammation Mediators; D053645:Interleukin-2 Receptor alpha Subunit; D053699:Interleukin-7 Receptor alpha Subunit; D054447:Receptors, CCR10; D054398:Receptors, CCR4; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D011991:Receptors, Virus; C409043:inecalcitol; D002762:Cholecalciferol