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.