Abstract
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.
Highlights
Regulatory Dendritic cells (DCs) are important in tolerance maintenance, whereas the mechanisms for maintaining their immunosuppressive function in immune microenvironment remain unclear
TGF--induced ERK Activation Is Responsible for the Higher Expression of Fas by Regulatory DCs—TNF superfamily receptors are expressed on a variety of cell types and play important roles in cell-cell interactions in the immune system [26]
Because TGF- has been shown to be important in Fas expression and ERK activation, we tested whether TGF- was responsible for the higher Fas expression on regulatory DCs compared with that on imDCs or mature DCs (maDCs)
Summary
Regulatory DCs are important in tolerance maintenance, whereas the mechanisms for maintaining their immunosuppressive function in immune microenvironment remain unclear. Conclusion: Fas signal, at least from activated T cells, enhances regulatory function of regulatory DCs. Significance: This study provides new mechanistic insight for immune homeostasis. 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 CD11bhiIalow 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. 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
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