1α,25-dihydroxyvitamin D3 has a direct effect on naive CD4+ T cells to enhance the development of Th2 cells
1α,25-dihydroxyvitamin D3 has a direct effect on naive CD4+ T cells to enhance the development of Th2 cells
复制标题
DOI：
10.4049/jimmunol.167.9.4974
复制
发表时间：
2001-11-01
影响因子：
4.4
通讯作者：
O'Garra, A
中科院分区：
文献类型：
--
作者：
Boonstra, A;Barrat, FJ;O'Garra, A
1 α，25-二羟基维生素D3（vitD 3）是一种免疫调节激素，对Th 1介导的自身免疫性疾病具有有益作用。虽然vitD 3对巨噬细胞和树突状细胞的抑制作用已被充分证明，但vitD 3对Th细胞发育的任何直接作用尚未明确定义。利用BALB/c和C57 BL/6遗传背景小鼠的CD 4（+）Mel 14（+）T细胞，我们检测了维生素D3对Th细胞发育的影响。我们证明，维生素D3通过抑制Th 1（IFN-γ产生）和增强Th 2细胞发育（IL-4，IL-5和IL-10产生）影响Th细胞极化。在用脾APC和Ag以及单独用抗CD 3和抗CD 28驱动的培养物中观察到这些效应，表明CD 4（+）细胞也可以是vitD 3的直接靶点。vitD 3对BALB/c和C57 BL/6小鼠Th 2细胞发育均有促进作用。Th 2特异性转录因子加塔-3和c-maf的表达增加与VitD 3处理后Th 2细胞因子的产生增加相关。维生素D3诱导的作用主要是通过IL-4介导的，因为IL-4的中和几乎完全消除了维生素D3治疗后增强的Th 2细胞发育。这些发现表明，维生素D3直接作用于Th细胞，并可以在APC的情况下，增强Th 2表型的发展和增加的转录因子c-maf和加塔-3的表达。我们的研究结果表明，维生素D3在自身免疫性疾病和移植中的有益作用是通过对APC的作用来预防强烈的Th 1应答，同时直接作用于T细胞以增强Th 2细胞的发育。
1 alpha ,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-gamma 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.