Fas signal links innate and adaptive immunity by promoting dendritic-cell secretion of CC and CXC chemokines

Abstract

IntroductionFas-FasL (Fas ligand) interaction has been long viewed as a means to achieve immune down-regulation by mediating apoptosis of activated T cells and other sensitive cells by providing immune privilege for organs such as eyes and testis, and by inhibiting immune response in the immune escape of tumors. [1][2][3][4] However, when FasL was transfected into various murine transplants, with the expectation that it would promote immune tolerance, it was found to cause neutrophil infiltration and to exacerbate allograft destruction. [5][6][7] Increasing evidence demonstrates that Fas ligation is involved in the induction of proinflammatory responses, eliciting secretion of proinflammatory cytokines (interleukin 1 [IL-1], tumor necrosis factor-␣) 8,9 and chemokines (IL-8, monocyte chemoattractant protein 1 , macrophage inflammatory protein 2 [MIP-2], keratinocyte-derived chemokine) [9][10][11][12][13] in various cell types, with or without apoptosis induction. It has been suggested that Fas-induced chemokines are directly responsible for neutrophil infiltration; however, there is no direct evidence supporting this hypothesis, and the mechanisms by which Fas signal induced chemokine production remain to be fully understood.Dendritic cells (DCs), professional antigen-presenting cells with a unique capacity to prime naive T cells, play an essential role in linking innate and adaptive immune responses. 14,15 In recent years, increasing data support the idea that DCs are resistant to Fas-mediated apoptosis, despite Fas expression on their surface. 16,17 Our previous work demonstrates that Fas ligation on DCs induces maturation and survival rather than apoptosis of DCs, consistent with the report of another group. 16 We also show that extracellular signal-regulated kinase (ERK) and nuclear factor-B (NF-B) pathways play different roles in Fas-induced DC maturation and survival. 18 Given that the proinflammatory function of Fas ligation is exerted in many cell types and chemokines are very important in the activation of innate and adaptive immunity, we wondered whether Fas signal can enhance chemokine production in DCs and whereby increase chemoattraction of immune cells around DCs, thus creating an ideal microenvironment for activation of adaptive immunity.In this study, we report that Fas ligation induces DCs to rapidly produce higher amounts of CXC and CC chemokines, including MIP-2, MIP-1␣, MIP-1␤, MCP-1, RANTES (regulated on activation normal T cell expressed and secreted), and TARC (thymus and activation-regulated chemokine). Fas-ligated DCs or their supernatant chemoattract more neutrophils as well as naive and activated CD4 ϩ , CD8 ϩ T cells in vivo and in vitro and enhance their functions. Moreover, Fas-induced chemokine production in DCs is transcription independent, but depends on the activation of Ras/Raf/ mitogen-activated protein kinase kinase (MEK)/ERK signaling and caspase cascades. Taken together, our data demonstrate that Fas ligation promotes DC chemokine production, which subsequently Materials a...

Blockade of Fas Signaling in Breast Cancer Cells Suppresses Tumor Growth and Metastasis via Disruption of Fas Signaling-initiated Cancer-related Inflammation

“…Our previous studies showed that Fas signaling could promote lung cancer growth by recruiting myeloid-derived suppressor cells (MDSCs) 4 in vivo (20), and the bioactive Fas ligand (FasL) released by activated T cells in exosomes could promote melanoma and lung cancer cell metastasis through Fas signaling (21). Furthermore, Fas ligation promotes not only survival but also an increase in maturation of dendritic cells (DCs) and induces DCs to rapidly produce both CXC and CC chemokines, which results in enhanced chemoattraction of neutrophils and T cells in vivo or in vitro (22,23). In some instances cytokines and chemokines can recruit antitumor immune effector cells so as to control tumor progression (24,25); however, cytokines and chemokines in the tumor microenvironment usually recruit immunosuppressive cells to help tumor escape immunological attack and promote angiogenesis (20 -21, 26).…”

Apoptosis and the homeostatic control of immune responses

“…This killing of DCs may also explain the profound immunosuppression observed after certain viral infections such as measles [19]. Conversely, perhaps Fas signaling has an additional effect on DCs, as indicated by induction of chemokine production by DCs stimulated with anti-Fas [20]. If this is so, autoimmunity induced by the DCs in these experiments may be caused by increased DC activity induced by the very signals which are normally dampened by their ability to also drive DC death.…”

TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells

“…Our previous studies have shown that chemokine gene transfer can enhance DC-mediated and T cell-dependent anti-tumor immunity and thus represents a potent anti-tumor immunotherapeutic approach. [35][36][37] Therefore, increased chemokine secretion by DAMP-stimulated DCs is expected to exert strong chemoattractant effects on DCs and T cells, resulting in improved protective immunity and an enhanced T-cell response.…”