Absence of vasoactive intestinal peptide expression in hematopoietic cells enhances Th1 polarization and antiviral immunity in mice.
Absence of vasoactive intestinal peptide expression in hematopoietic cells enhances Th1 polarization and antiviral immunity in mice.
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DOI：
10.4049/jimmunol.1100686
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发表时间：
2011-07-15
期刊：
影响因子：
--
通讯作者：
Waller EK
中科院分区：
文献类型：
--
作者：
Li JM;Southerland L;Hossain MS;Giver CR;Wang Y;Darlak K;Harris W;Waschek J;Waller EK
血管活性肠肽(VIP)在体外诱导调节性树突状细胞(DC)，抑制细胞免疫反应。我们利用VIP基因敲除(VIP-KO)小鼠和植入同源VIP-KO造血细胞的放射嵌合体，检测了生理水平的VIP在小鼠巨细胞病毒(MCMV)免疫应答中的作用。与野生型小鼠(WT)相比，感染MCMV后，VIP-KO小鼠体重减轻较少，存活率较高。感染巨细胞病毒的VIPKO小鼠病毒载量较低，病毒清除较快，γ+NK细胞和NKT细胞数量增加，NK细胞杀伤活性增强。与WT小鼠相比，感染MCMV的VIP-KO小鼠的获得性抗病毒细胞免疫功能增强，Th1/Tc1极化T细胞增多，IL-10+T细胞减少，MCMV-M45表位多肽-MHC I类四聚体+CD8+T细胞增多(四聚体+CD8T细胞)。MCMV免疫的VIP-KO小鼠体内清除MCMV多肽冲击的靶细胞的能力增强。移植VIP-KO造血细胞的WT移植受者抗病毒免疫功能增强，表明神经细胞合成的VIP不抑制免疫反应。MCMV感染后，VIP-KO小鼠DC表面MHC-II类(MHC-II)和CD80共刺激分子的表达显著高于WT小鼠DC，而活化的CD8+T细胞和DC的PD-1和PD-L1表达分别上调，而VIP-KO小鼠则不表达。由于免疫细胞中缺乏VIP可通过改变共刺激和共抑制途径来增强先天和获得性抗病毒免疫，因此选择性靶向VIP信号转导是增强抗病毒免疫的一个有吸引力的治疗靶点。
Vasoactive intestinal peptide (VIP) induces regulatory dendritic cells (DC) in vitro that inhibit cellular immune responses. We tested the role of physiological levels of VIP on immune responses to murine cytomegalovirus (mCMV) using VIP-knockout (VIP-KO) mice and radiation chimeras engrafted with syngenic VIP-KO hematopoietic cells. VIP-KO mice and had less weight loss and better survival following mCMV infection compared with wild-type littermates (WT). MCMV-infected VIP-KO mice had lower viral loads, faster clearance of virus, with increased numbers of IFN-γ+ NK and NKT cells, and enhanced cytolytic activity of NK cells. Adaptive anti-viral cellular immunity was increased in mCMV-infected VIP-KO mice compared with WT mice, with more Th1/Tc1 polarized T-cells, fewer IL-10+ T-cells, and more mCMV-M45 epitope peptide-MHC class I-tetramer+ CD8+ T-cells (tetramer+ CD8 T-cells). MCMV-immune VIP-KO mice had enhanced ability to clear mCMV-peptide pulsed target cells in vivo. Enhanced anti-viral immunity was also seen in WT transplant recipients engrafted with VIP-KO hematopoietic cells, indicating that VIP synthesized by neuronal cells did not suppress immune responses. Following mCMV infection there was a marked up-regulation of MHC class II (MHC-II) and CD80 co-stimulatory molecule expression on DC from VIP-KO mice compared with DC from WT mice, while PD-1 and PD-L1 expression were up-regulated in activated CD8+ T-cells and DC, respectively, in WT mice but not in VIP-KO mice. Since the absence of VIP in immune cells increased innate and adaptive anti-viral immunity by altering co-stimulatory and co-inhibitory pathways, selective targeting of VIP-signaling represents an attractive therapeutic target to enhance anti-viral immunity.
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影响因子：
30.5
作者：
Andrews, DM;Andoniou, CE;Degli-Esposti, MA
通讯作者：
Degli-Esposti, MA
影响因子：
5.3
作者：
Herrera JL;Gonzalez-Rey E;Fernandez-Montesinos R;Quintana FJ;Najmanovich R;Pozo D
通讯作者：
Pozo D
影响因子：
4.7
作者：
Girard, Beatrice A.;Lelievre, Vincent;May, Victor
通讯作者：
May, Victor
影响因子：
4.4
作者：
Gold, MC;Munks, MW;Fling, SP
通讯作者：
Fling, SP
DOI：
10.1073/pnas.0406035101
发表时间：
2004-09-21
影响因子：
11.1
作者：
Brockstedt, DG;Giedlin, MA;Dubensky, TW
通讯作者：
Dubensky, TW