Signal Transduction in DC Differentiation: Winged Messengers and Achilles’ Heel

Lindner, Inna; Cejas, Pedro J.; Carlson, Louise; Torruellas, Julie; Plano, Gregory V.; Lee, Kelvin P.

doi:10.1007/978-0-387-34814-8_1

Cited by 8 publications

(7 citation statements)

References 162 publications

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“…Because NF‐κB is a key transcription factor responsible for DC activation 18, 19, we next examined whether Tim‐1 signaling could induce DC maturation in terms of the expression of surface molecules and the production of cytokines. Compared with the control rIgG2a treatment, treatment with agonistic/high‐avidity anti‐Tim‐1 3B3 resulted in marked upregulation of MHC class II, CD80, and CD86 on DCs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Tim‐1 stimulation of dendritic cells regulates the balance between effector and regulatory T cells

et al. 2011

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Summary We show that Tim-1, initially reported to be expressed on CD4+ T cells, is constitutively expressed on dendritic cells (DC) and that its expression further increases after DC maturation. Tim-1 signaling into DC upregulates costimulatory molecule expression and proinflammatory cytokine production, thereby promoting effector T cell responses, while inhibiting Foxp3+ Treg responses. By contrast, Tim-1 signaling in T cells only regulates Th2 responses. Using a high-avidity/agonistic anti-Tim-1 antibody as a co-adjuvant enhances the immunogenic function of DC, decreases the suppressive function of Treg cells, and substantially increases proinflammatory Th17 responses in vivo. The treatment with high-but not low-, avidity anti-Tim-1 not only worsens experimental autoimmune encephalomyelitis (EAE) in susceptible mice but also breaks tolerance and induces EAE in a genetically resistant strain of mice. These findings indicate that Tim-1 has an important role in regulating DC function, and thus shifts the balance between effector and regulatory T cells towards an enhanced immune response. By understanding the mechanisms by which Tim-1 regulates DC and T cell responses, we may clarify the potential utility of Tim-1 as a target of therapy against autoimmunity, cancer and infectious diseases.

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Section: Resultsmentioning

confidence: 99%

Tim‐1 stimulation of dendritic cells regulates the balance between effector and regulatory T cells

et al. 2011

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“…We questioned whether the EPO treatment of BM-DCs activates signal transduction pathways that participate in DC activation (Lindner et al, 2007;Rescigno et al, 1998) 13 and thus focused on the NF-κB, MAPK and AKT pathways. BM-DCs were stimulated with 50 U/ml rHuEPO or with 0.05 µg/ml LPS (positive control) for the indicated time periods and cell lysates were subjected to immunoblot analysis.…”

Section: Epo Leads To Activation Of Multiple Signaling Pathways In DCmentioning

confidence: 99%

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

Lifshitz

Prutchi-Sagiv

Avneon

et al. 2009

Molecular Immunology

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Erythropoietin (EPO) is the main hormone that promotes proliferation and differentiation of erythroid progenitor cells via binding to its surface receptor (EPO-R). Recent studies suggest that this hormone may affect also other cell types, besides the red blood cell lineage. We have previously demonstrated that the immune system is a target of EPO; however, the direct target cells of EPO, as well as the molecular mechanisms underlying its role as an immunomodulator, are unknown. Here we present evidence for functional effects of EPO on dendritic cells (DCs), which are known to initiate the immune response. In-vivo experiments in EPO-injected mice and in transgenic mice over-expressing human EPO showed an increased splenic DC population with a higher cell surface expression of CD80 and CD86. Further analysis based on mouse models, showed that DCs derived in-vitro from bone marrow (BM-DCs) express EPO-R mRNA. In-vitro stimulation of these DCs with recombinant human EPO enhanced viability, upregulated CD80, CD86 and MHC class II and augmented the secretion of IL-12. Biochemical analysis of EPO mediated signaling in the BM-DCs showed activation of the AKT, MAPK and NF-kappaB pathways. EPO stimulation of the BM-DCs led to Tyr-phosphorylation of STAT3. The inability to detect EPO mediated activation of STAT5 in the BM-DCs, suggests that in DCs, STAT3 may play a more important role than STAT5 in EPO-R signaling. Taken together, our data support the premise that DCs are direct targets of EPO, thereby providing an insight to the immunomodulatory functions of EPO.

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“…For example, recognition of lipopolysaccharide (LPS), an essential component of Gram-negative bacteria, activates one member of a family of PRRs known as toll-like receptor (TLR) 4, which in turn leads to a series of signaling events culminating in the activation of a transcription factor crucial for the host response: nuclear factor (NF)-B. This transcription factor up-regu-lates a wide variety of inflammatory genes, including CD40, CD54 (ICAM-1), tumor necrosis factor (TNF)-␣, and interleukin (IL)-1␤, as well as Th1 skewing cytokines such as IL-12 (5)(6)(7)(8).…”

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confidence: 99%

Annexin‐1‐deficient dendritic cells acquire a mature phenotype during differentiation

et al. 2008

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Dendritic cells play a key role in the adaptive immune system by influencing T-cell differentiation. Annexin-1 (Anx-A1) has recently been shown to modulate the adaptive immune response by regulating T-cell activation and differentiation. Here we investigated the role of endogenous Anx-A1 in dendritic cells as major cellular counterpart of T-cell-driven immune response. We found that Anx-A1(-/-) bone marrow-derived dendritic cells show an increased number of CD11c(+) cells expressing high levels of some maturation markers, such as CD40, CD54, and CD80, coupled to a decreased capacity to take up antigen compared to control Anx-A1(+/+) cells. However, analysis of LPS-treated dendritic cells from Anx-A1(-/-) mice demonstrated a diminished up-regulation of maturation markers, a decreased migratory activity in vivo, and an attenuated production of the inflammatory cytokines interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and IL-12. This defect was also accompanied by impaired nuclear factor (NF)-kappaB/DNA-binding activity and lack of Anx-A1 signaling, as demonstrated by the reduced activation of extracellular-signal regulated kinase (ERK)1/2 and Akt compared to cells from control littermates. As a consequence of this phenotype, Anx-A1(-/-) dendritic cells showed an impaired capacity to stimulate T-cell proliferation and differentiation in mixed leukocyte reaction. Together, these findings suggest that inhibition of Anx-A1 expression or function in dendritic cells might represent a useful way to modulate the adaptive immune response and pathogen-induced T-cell-driven immune diseases.

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Signal Transduction in DC Differentiation: Winged Messengers and Achilles’ Heel

Cited by 8 publications

References 162 publications

Tim‐1 stimulation of dendritic cells regulates the balance between effector and regulatory T cells

Tim‐1 stimulation of dendritic cells regulates the balance between effector and regulatory T cells

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

Annexin‐1‐deficient dendritic cells acquire a mature phenotype during differentiation

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