Bcl6 Is Required for the Development of Mouse CD4+ and CD8α+ Dendritic Cells
Bcl6 Is Required for the Development of Mouse CD4+ and CD8α+ Dendritic Cells
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DOI：
10.4049/jimmunol.0903714
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发表时间：
2011-01-01
影响因子：
4.4
通讯作者：
Tokuhisa, Takeshi
中科院分区：
文献类型：
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作者：
Ohtsuka, Hiromi;Sakamoto, Akemi;Tokuhisa, Takeshi
在Bcl 6敲除（KO）小鼠中自发显示的Th 2型炎症主要由骨髓（BM）来源的非淋巴细胞引起。然而，树突状细胞（DCs）在Bcl 6-KO小鼠中的功能尚未报道。我们在这篇文章中显示，在Bcl 6-KO小鼠的脾脏中，CD 4（+）常规DC（cDC）和CD 8 α（+）cDC的数量显著减少，但浆细胞样DC的数量没有减少。从BM细胞中的DC祖细胞产生cDC在用Bcl 6-KO BM细胞转移的经辐照的野生型（WT）小鼠的脾中受到干扰，表明Bcl 6在cDC前体中的内在作用。尽管cDC前体在具有Fms样酪氨酸激酶3配体的Bcl 6-KO BM培养物中产生，但cDC前体比WT前体更凋亡。此外，Bcl 6的分子靶点之一p53在前体中过表达。向Bcl 6-KO BM培养物中添加p53抑制剂保护了凋亡，表明Bcl 6是cDC前体通过控制p53表达而存活所需的。此外，Bcl 6-KO小鼠的脾脏中自然发育了大量T1/ST 2（+）Th 2细胞。在用Ag和LPS活化的Bcl 6-KO BM衍生的DC刺激的WT CD 4 T细胞的培养物中，Th 2偏斜加速，其产生比WT DC更多的IL-6和更少的IL-12;向培养物中加入抗IL-6 Ab部分消除了Th 2偏斜。这些结果表明，Bcl 6是必需的cDC前体中的存活和活化的DC中用于调节细胞因子谱。免疫学杂志，2011，186：255-263。
Th2-type inflammation spontaneously shown in Bcl6-knockout (KO) mice is mainly caused by bone marrow (BM)-derived non-lymphoid cells. However, the function of dendritic cells (DCs) in Bcl6-KO mice has not been reported. We show in this article that the numbers of CD4(+) conventional DCs (cDCs) and CD8 alpha(+) cDCs, but not of plasmacytoid DCs, were markedly reduced in the spleen of Bcl6-KO mice. Generation of cDCs from DC progenitors in BM cells was perturbed in the spleen of irradiated wild-type (WT) mice transferred with Bcl6-KO BM cells, indicating an intrinsic effect of Bcl6 in cDC precursors. Although cDC precursors were developed in a Bcl6-KO BM culture with Fms-like tyrosine kinase 3 ligand, the cDC precursors were more apoptotic than WT ones. Also p53, one of the molecular targets of Bcl6, was overexpressed in the precursors. The addition of a p53 inhibitor to Bcl6-KO BM culture protected apoptosis, suggesting that Bcl6 is required by cDC precursors for survival by controlling p53 expression. Furthermore, large numbers of T1/ST2(+) Th2 cells were naturally developed in the spleen of Bcl6-KO mice. Th2 skewing was accelerated in the culture of WT CD4 T cells stimulated with Ags and LPS-activated Bcl6-KO BM-derived DCs, which produced more IL-6 and less IL-12 than did WT DCs; the addition of anti-IL-6 Abs to the culture partially abrogated the Th2 skewing. These results suggest that Bcl6 is required in cDC precursors for survival and in activated DCs for modulating the cytokine profile. The Journal of Immunology, 2011, 186: 255-263.