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,25-Dihydroxyvitamin D3 Has a Direct Effect on Naive CD4+ T Cells to Enhance the Development of Th2 Cells1
,
*
Department of Immunology, DNAX Research Institute, Palo Alto, CA 94304;
Department of Immunology, Erasmus University and University Hospital Rotterdam, Rotterdam, The Netherlands;
Department of Cell Biology and Immunology, Wageningen University, Wageningen, The Netherlands
1
,25-Dihydroxyvitamin D3 (vitD3) is an immunoregulatory hormone
with beneficial effects on Th1 mediated autoimmune diseases. Although
the inhibitory effects of vitD3 on macrophages and dendritic cells are
well documented, any direct effects of vitD3 on Th cell development are
not clearly defined. Using CD4+Mel14+ T cells
derived from mice on a BALB/c and a C57BL/6 genetic background we
examined the effect of vitD3 on Th cell development. We demonstrated
that vitD3 affects Th cell polarization by inhibiting Th1 (IFN-
production) and augmenting Th2 cell development (IL-4, IL-5, and IL-10
production). These effects were observed in cultures driven with
splenic APC and Ag, as well as with anti-CD3 and anti-CD28
alone, indicating that CD4+ cells can also be direct
targets for vitD3. The enhanced Th2 development by vitD3 was found in
both BALB/c and C57BL/6 mice. An increased expression of the
Th2-specific transcription factors GATA-3 and c-maf
correlated with the increased production of Th2 cytokines after vitD3
treatment. The vitD3-induced effects were largely mediated via IL-4,
because neutralization of IL-4 almost completely abrogated the
augmented Th2 cell development after vitD3 treatment. These findings
suggest that vitD3 acts directly on Th cells and can, in the absence of
APC, enhance the development of a Th2 phenotype and augment the
expression of the transcription factors c-maf and
GATA-3. Our findings suggest that the beneficial effects of vitD3 in
autoimmune diseases and transplantation operate through prevention of
strong Th1 responses via the action on the APC, while simultaneously
directly acting on the T cell to enhance Th2 cell
development.
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