DC apoptosis has been observed in patients with cancer and sepsis, and defects in DC apoptosis have been implicated in the development of autoimmune diseases. However, the mechanisms of how DC apoptosis affects immune responses, are unclear. In this study, we showed that immature viable DC have the ability to uptake apoptotic DC as well as necrotic DC without it being recognized as an inflammatory event by immature viable DC. However, the specific uptake of apoptotic DC converted immature viable DC into tolerogenic DC, which were resistant to LPS-induced maturation. These tolerogenic DC secreted increased levels of TGF-b1, which induced differentiation of naïve T cells into Foxp3 1 Treg. Furthermore, induction of Treg differentiation only occurred upon uptake of apoptotic DC and not apoptotic splenocytes by viable DC, indicating that it is specifically the uptake of apoptotic DC that gives viable immature DC the potential to induce Foxp3 1 Treg. Taken together, these findings identify uptake of apoptotic DC by viable immature DC as an immunologically tolerogenic event.Key words: Apoptosis . Autoimmunity . DC . Tolerance Introduction DC are professional antigen-presenting cells, which are well positioned in peripheral tissues to capture foreign antigens. DC are phagocytic and can ingest apoptotic cells, and hence are affected by the death of other cells in close proximity [1][2][3]. Clearance of apoptotic cells results in their removal from tissues, and provides protection from release of pro-inflammatory contents. Necrotic cells impact the immune response by acting as ''danger signals'', whereas apoptotic cells are cleared without an immunological response [3,4]. Studies have identified necrotic cells acting as adjuvants, whereas apoptotic cells have been reported as immunogenic [5][6][7] or immunosuppressive [8,9]. DC apoptosis in itself is an important event for maintenance of tolerance. Defects in DC apoptosis have been linked to the development of autoimmunity with systemic autoimmune diseases modeled in transgenic mice harboring defects in DC apoptosis [10] but not in mice with apoptosis defects in T and B cells [11][12][13]. However, it is unclear how defects in DC apoptosis 1022can trigger autoimmune responses. Furthermore, spontaneous DC apoptosis has been reported in sepsis as well as breast cancer patients with its significance being unclear [14][15][16]. Most patient deaths associated with sepsis occur at later time points and are associated with prolonged immunosuppression [17]. In this later stage, there is marked apoptosis of DC, with no effects on macrophage and neutrophil apoptosis. In addition, immunostimulants such as CpG DNA inhibit DC apoptosis [18], whereas the deficiency of pro-apoptotic Bim protein in DC results in autoimmunity [19].Immature DC have the ability to acquire protein complexes or soluble antigen using many different pathways such as macropinocytosis, endocytosis and even through ingestion of entire cells. Despite the importance of DC apoptosis in the immune response, studies ...

The E26 transformation-specific (ETS) family of transcription factors comprises of 27 and 26 members in humans and mice, respectively, which are known to regulate many different biological processes, including cell proliferation, cell differentiation, embryonic development, neoplasia, hematopoiesis, angiogenesis, and inflammation. The epitheliumspecific ETS transcription factor-1 (ESE-1) is a physiologically important ETS transcription factor, which has been shown to play a role in the pathogenesis of various diseases, and was originally characterized as having an epithelial-restricted expression pattern, thus placing it within the epithelium-specific ETS subfamily. Despite a large body of published work on ETS biology, much remains to be learned about the precise functions of ESE-1 and other epithelium-specific ETS factors in regulating diverse disease processes. Clues as to the specific function of ESE-1 in the setting of various diseases can be obtained from studies aimed at examining the expression of putative target genes regulated by ESE-1. Thus, this review will focus primarily on the various roles of ESE-1 in different pathophysiological processes, including regulation of epithelial cell differentiation during both intestinal development and lung regeneration; regulation of dendritic cell-driven T-cell differentiation during allergic airway inflammation; regulation of mammary gland development and breast cancer; and regulation of the effects of inflammatory stimuli within the setting of synovial joint and vascular inflammation. Understanding the exact mechanisms by which ESE-1 regulates these processes can have important implications for the treatment of a wide range of diseases. KEYWORDS: cancer; development; epithelial cell differentiation; ESE-1; ETS transcription factor; inflammation; regeneration The E26 transformation-specific (ETS) family of transcription factors is characterized by a highly conserved 84-aminoacid DNA-binding domain, known as the ETS domain. 1 Because the first member of the ETS family, the v-ets oncogene, was originally discovered as part of a fusion protein with gag and myb expressed by the E26 avian erythroblastosis-transforming retrovirus and its DNA-binding domain is E26 transformation-specific, this 84-amino-acid DNA-binding domain was named the ETS domain. 1 The ETS domain is usually located within the carboxyl-terminal region of the protein as a winged helix-turn-helix structural motif and mediates binding to sites of purine-rich DNA, commonly containing a core consensus sequence of GGAA/T, within the promoter and enhancer regions of target genes. 2,3 Many ETS transcription factors also contain a pointed domain, which is located within the amino-terminal region and is involved in protein-protein interactions. 2 Approximately 30 members of the ETS transcription factor family have been identified in mammals (ie 27 in humans and 26 in mice), 4 and have been shown to play crucial roles in the regulation of many physiological and pathological processes, such as embryonic develo...

Dendritic cell (DC) apoptosis has been shown to play a role in maintaining a balance between tolerance and immunity. However, the mechanisms of how DC apoptosis affects the immune response are unclear. We have shown that in vitro culture of apoptotic DCs with immature DCs, results in their uptake by immature DCs, which subsequently turn into tolerogenic DCs, which then secrete TGF-β1 and induce Foxp3+ regulatory T cells (Tregs). In this study we looked at the effects of apoptotic DCs in vivo. Here we show that apoptotic DCs are taken up by viable DCs in vivo, which suppresses the ability of viable DCs to undergo maturation and subsequent migration to the lymph nodes in response to LPS. Additionally, delivery of apoptotic DCs to LPS inflamed lungs results in resolution of inflammation, which is mediated by the ability of apoptotic DCs to suppress response of viable DCs to LPS. Additionally, apoptotic DCs also induce TGF-β1 secretion in the mediastinal lymph nodes, which results in expansion of Foxp3+ Tregs. Most importantly, we show that delivery of apoptotic DCs followed by OVA in CFA to mice suppresses T cell response to OVA and instead induces de novo generation of OVA-specific Tregs. Furthermore, delivery of apoptotic DCs followed by OVA in CFA results in expansion of Tregs in TCR transgenic (OT-II) mice. These findings demonstrate that apoptotic DCs are taken up by viable DCs in vivo, which promotes tolerance through suppression of DC maturation and induction of Tregs.

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