Fas signal promotes the immunosuppressive function of regulatory dendritic cells via the ERK/β-catenin pathway.
Dendritic cells (DCs) play important roles in the initiation of immune response and also in the maintenance of immune tolerance. Now, many kinds of regulatory DCs with different phenotypes have been identified to suppress immune response and contribute to the control of autoimmune diseases. However, the mechanisms by which regulatory DCs can be regulated to exert the immunosuppressive function in the immune microenvironment remain to be fully investigated. In addition, how T cells, once activated, can feedback affect the function of regulatory DCs during immune response needs to be further identified. We previously identified a unique subset of CD11b(hi)Ia(low) regulatory DCs, differentiated from mature DCs or hematopoietic stem cells under a stromal microenvironment in spleen and liver, which can negatively regulate immune response in a feedback way. Here, we show that CD11b(hi)Ia(low) regulatory DCs expressed high level of Fas, and endothelial stromal cell-derived TGF-β could induce high expression of Fas on regulatory DCs via ERK activation. Fas ligation could promote regulatory DCs to inhibit CD4(+) T cell proliferation more significantly. Furthermore, Fas ligation preferentially induced regulatory DCs to produce IL-10 and IP-10 via ERK-mediated inactivation of GSK-3 and subsequent up-regulation of β-catenin. Interestingly, activated T cells could promote regulatory DCs to secrete more IL-10 and IP-10 partially through FasL. Therefore, our results demonstrate that Fas signal, at least from the activated T cells, can promote the immunosuppressive function of Fas-expressing regulatory DCs, providing a new manner for the regulatory DCs to regulate adaptive immunity.
From the National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
Cheng
C
Qian
Li
L
Qian
Yizhi
Y
Yu
Huazhang
H
An
Zhenhong
Z
Guo
Yanmei
Y
Han
Yongjian
Y
Chen
Yi
Y
Bai
Qingqing
Q
Wang
Xuetao
X
Cao
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D054357:Chemokine CXCL10 / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006706:Homeostasis; D007107:Immune System; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
D054357:Chemokine CXCL10; C491899:Fas protein, mouse; D051176:beta Catenin; D019014:fas Receptor; D016753:Interleukin-10; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3
Catenin; Dendritic Cells; ERK; Fas; Tolerance