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论文题目: The Notch Ligand DLL4 Defines a Capability of Human Dendritic Cells in Regulating Th1 and Th17 Differentiation
英文论文题目: The Notch Ligand DLL4 Defines a Capability of Human Dendritic Cells in Regulating Th1 and Th17 Differentiation
第一作者: Meng, LJ; Bai, ZJ; He, S; Mochizuki, K; Liu, YN; Purushe, J; Sun, HX; Wang, J; Yagita, H; Mineishi, S; Fung, H; Yanik, GA; Caricchio, R; Fan, XX; Crisalli, LM; Hexner, EO; Reshef, R; Zhang, YY; Zhang, Y
英文第一作者: Meng, LJ; Bai, ZJ; He, S; Mochizuki, K; Liu, YN; Purushe, J; Sun, HX; Wang, J; Yagita, H; Mineishi, S; Fung, H; Yanik, GA; Caricchio, R; Fan, XX; Crisalli, LM; Hexner, EO; Reshef, R; Zhang, YY; Zhang, Y
联系作者: Zhang, YY (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Key Lab Stem Cell Biol, Shanghai 200231, Peoples R China.
英文联系作者: Zhang, YY (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Key Lab Stem Cell Biol, Shanghai 200231, Peoples R China.
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发表年度: 2016
卷: 196
期: 3
页码: 1070-1080
摘要: Notch signaling regulates multiple helper CD4(+) T cell programs. We have recently demonstrated that dendritic cells (DCs) expressing the Notch ligand DLL4 are critical for eliciting alloreactive T cell responses and induction of graft-versus-host disease in mice. However, the human counterpart of murine DLL4(+) DCs has yet to be examined. We report the identification of human DLL4(+) DCs and their critical role in regulating Th1 and Th17 differentiation. CD1c(+) DCs and plasmacytoid DCs (pDCs) from the peripheral blood (PB) of healthy donors did not express DLL4. In contrast, patients undergoing allogeneic hematopoietic stem cell transplantation had a 16-fold more DLL4(+)CD1c(+) DCs than healthy donors. Upon activation of TLR signaling, healthy donor derived CD1c+ DCs dramatically upregulated DLL4, as did pDCs to a lesser extent. Activated DLL4(+) DCs were better able to promote Th1 and Th17 differentiation than unstimulated PB DCs. Blocking DLL4 using a neutralizing Ab decreased Notch signaling in T cells stimulated with DLL4(+) DCs, and it reduced the generation of Thl and Th17 cells. Both NF-kappa B and STAT3 were crucial for inducing DLL4 in human DCs. Interestingly, STAT3 directly activated DLL4 transcription and inhibiting STAT3 alone was sufficient to reduce DLL4 in activated PB DCs. Thus, DLL4 is a unique functional molecule of human circulating DCs critical for directing Thl and Th17 differentiation. These findings identify a pathway for therapeutic intervention for inflammatory disorders in humans, such as graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, autoimmunity, and tumor immunity.
英文摘要: Notch signaling regulates multiple helper CD4(+) T cell programs. We have recently demonstrated that dendritic cells (DCs) expressing the Notch ligand DLL4 are critical for eliciting alloreactive T cell responses and induction of graft-versus-host disease in mice. However, the human counterpart of murine DLL4(+) DCs has yet to be examined. We report the identification of human DLL4(+) DCs and their critical role in regulating Th1 and Th17 differentiation. CD1c(+) DCs and plasmacytoid DCs (pDCs) from the peripheral blood (PB) of healthy donors did not express DLL4. In contrast, patients undergoing allogeneic hematopoietic stem cell transplantation had a 16-fold more DLL4(+)CD1c(+) DCs than healthy donors. Upon activation of TLR signaling, healthy donor derived CD1c+ DCs dramatically upregulated DLL4, as did pDCs to a lesser extent. Activated DLL4(+) DCs were better able to promote Th1 and Th17 differentiation than unstimulated PB DCs. Blocking DLL4 using a neutralizing Ab decreased Notch signaling in T cells stimulated with DLL4(+) DCs, and it reduced the generation of Thl and Th17 cells. Both NF-kappa B and STAT3 were crucial for inducing DLL4 in human DCs. Interestingly, STAT3 directly activated DLL4 transcription and inhibiting STAT3 alone was sufficient to reduce DLL4 in activated PB DCs. Thus, DLL4 is a unique functional molecule of human circulating DCs critical for directing Thl and Th17 differentiation. These findings identify a pathway for therapeutic intervention for inflammatory disorders in humans, such as graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, autoimmunity, and tumor immunity.
刊物名称: JOURNAL OF IMMUNOLOGY
英文刊物名称: JOURNAL OF IMMUNOLOGY
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学科: Immunology
英文学科: Immunology
影响因子: 4.856
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论文类别: Article
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