Apoptotic cells induce dendritic cell‐mediated suppression via interferon‐γ‐induced IDO

Williams, Charlotte A.; Harry, Rachel A.; McLeod, Julie

doi:10.1111/j.1365-2567.2007.02743.x

Cited by 67 publications

(53 citation statements)

References 61 publications

(97 reference statements)

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“…Therefore, it is likely that RhoA induces PI3K which phosphorylates mTOR resulting in release of eIF4E, which further results in increased translation of TGF-b1 mRNA. Some studies have indicated that another mechanism whereby DC can acquire tolerogenic potential is through induction of IDO [28,29]. Our results show no upregulation of IDO upon uptake of apoptotic DC by viable DC, indicating that induction of IDO is likely not the underlying mechanism for tolerance induction (data not shown).…”

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confidence: 39%

Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3⁺ Treg

et al. 2010

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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 ...

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confidence: 39%

Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3⁺ Treg

et al. 2010

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“…IDO activity can be induced by TGF-β (12), and apoptotic cells can induce IDO expression in bone marrow-derived DC coculture in vitro (14,15). Thus, we hypothesized that apoptotic cells might induce IDO expression in phagocytes after engulfment in vivo.…”

Section: Resultsmentioning

confidence: 99%

“…IDO expression can be induced in MΦs, DCs, and stromal cells by a variety of stimuli including Toll-like receptor ligation with subsequent IFN production (α and γ) and IDO functional activity is induced and enhanced by TGF-β (10,(12)(13)(14). Moreover, apoptotic cells can induce IDO in bone marrow-derived DCs by an IFN-γ-driven mechanism in vitro (15). However, it is not known what the relevance of this finding is for either apoptotic celldriven IDO expression or immune suppression in vivo.…”

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confidence: 99%

“…Administering apoptotic cells to mice generally promotes anti-inflammatory responses and immune tolerance (2, 8). However, if mice are depleted of MZMs, then challenge with apoptotic cells elicits a proinflammatory cytokine response, resulting in fulminate autoimmunity (7).IDO activity can be induced by TGF-β (12), and apoptotic cells can induce IDO expression in bone marrow-derived DC coculture in vitro (14,15). Thus, we hypothesized that apoptotic cells might induce IDO expression in phagocytes after engulfment in vivo.…”

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confidence: 99%

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Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase

Ravishankar

Liu²,

Shinde³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

174

210

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Tolerance to self-antigens present in apoptotic cells is critical to maintain immune-homeostasis and prevent systemic autoimmunity. However, mechanisms that sustain self-tolerance are poorly understood. Here we show that systemic administration of apoptotic cells to mice induced splenic expression of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO). IDO expression was confined to the splenic marginal zone and was abrogated by depletion of CD169 + cells. Pharmacologic inhibition of IDO skewed the immune response to apoptotic cells, resulting in increased proinflammatory cytokine production and increased effector T-cell responses toward apoptotic cell-associated antigens. Presymptomatic lupus-prone MRL lpr/lpr mice exhibited abnormal elevated IDO expression in the marginal zone and red pulp and inhibition of IDO markedly accelerated disease progression. Moreover, chronic exposure of IDO-deficient mice to apoptotic cells induced a lupus-like disease with serum autoreactivity to double-stranded DNA associated with renal pathology and increased mortality. Thus, IDO limits innate and adaptive immunity to apoptotic self-antigens and IDO-mediated regulation inhibits inflammatory pathology caused by systemic autoimmune disease.inflammation | macrophage M acrophages (MΦ) are innate scavenging cells that are important in maintenance of tolerance to self. Mechanistically, it is unknown how MΦs contribute to self-tolerance although it is evident that clearance is necessary and must lead to regulation rather than adaptive immunity. In this vein it has been shown that interaction of apoptotic cells with MΦs results in the induction of an anti-inflammatory response dominated by TGF-β, which suppresses proinflammatory cytokine production (1, 2). However, the molecular mechanisms by which capture of apoptotic cells trigger immune suppression in vivo is unknown. Moreover, known mechanisms, such as exposure of phosphatidyl serine and TGF-β production, do not explain how tolerance is maintained at the molecular level.Apoptotic cells in circulation are trapped and removed in the marginal zone (MZ) of the spleen (3). The MZ is populated by specialized MΦs tightly associated with the reticular meshwork. These MΦ are defined by constitutive expression of either the scavenger macrophage receptor with collagenous structure, MARCO, or the metallophillic macrophage marker, MOMA-1 (4-6). The importance of MZ MΦs (MZMs) in apoptotic cell removal and tolerance was illustrated by our recent findings that their depletion significantly changed the immune response to apoptotic cells altering localization, increasing proinflammatory cytokine production, and enhancing phagocytosis and phagocyte activation (7). Similarly, in related studies deletion of MARCO + and MOMA-1 + MZMs retarded the clearance of apoptotic material and abrogated tolerance to apoptotic cell-associated antigens in a mouse model of experimental autoimmune encephalomyelitis (8). Thus, defective MZM-mediated apoptotic cell capture and removal appears to have sig...

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“…Propagation of tolerogenic BMDCs with GM-CSF and IL-4 also results in higher production of IFN-g. 56 IFN-g production by DCs within an inflammatory environment has also been suggested to induce antiinflammatory indoleamine 2,3-dioxygenase. 57 In our preliminary studies, neutralization of IFN-g abrogated the immunosuppressive BMDC-induced protection after kidney IRI (data not shown). Future studies will be done to better understand the functional immunosuppressive role of CD11c + -derived IFN-g.…”

Section: /2mentioning

confidence: 99%

Sphingosine 1-Phosphate Receptor 3–Deficient Dendritic Cells Modulate Splenic Responses to Ischemia-Reperfusion Injury

Bajwa

Huang

Kurmaeva

et al. 2016

Journal of the American Society of Nephrology

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The plasticity of dendritic cells (DCs) permits phenotypic modulation ex vivo by gene expression or pharmacologic agents, and these modified DCs can exert therapeutic immunosuppressive effects in vivo through direct interactions with T cells, either inducing T regulatory cells (T REG s) or causing anergy. Sphingosine 1-phosphate (S1P) is a sphingolipid and the natural ligand for five G protein-coupled receptors (S1P1, S1P2, S1P3, S1P4, and S1P5), and S1PR agonists reduce kidney ischemia-reperfusion injury (IRI) in mice. S1pr3 2/2 mice are protected from kidney IRI, because DCs do not mature. We tested the therapeutic advantage of S1pr3 2/2 bone marrow-derived dendritic cell (BMDC) transfers in kidney IRI. IRI produced a rise in plasma creatinine (PCr) levels in mice receiving no cells (NCs) and mice pretreated with wild-type (WT) BMDCs. However, S1pr3 2/2 BMDC-pretreated mice were protected from kidney IRI. S1pr3 2/2BMDC-pretreated mice had significantly higher numbers of splenic T REG s compared with NC and WT BMDC-pretreated mice. S1pr3 2/2 BMDCs did not attenuate IRI in splenectomized, Rag-1 2/2 , or CD11c + DC-depleted mice. Additionally, S1pr3 2/2 BMDC-dependent protection required CD169 + marginal zone macrophages and the macrophage-derived chemokine CCL22 to increase splenic CD4 + Foxp3 + T REG s.Pretreatment with S1pr3 2/2 BMDCs also induced T REG -dependent protection against IRI in an allogeneic mouse model. In summary, adoptively transferred S1pr3 2/2 BMDCs prevent kidney IRI through interactions within the spleen and expansion of splenic CD4 + Foxp3 + T REG s. We conclude that genetically induced deficiency of S1pr3 in allogenic BMDCs could serve as a therapeutic approach to prevent IRI-induced AKI.

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Apoptotic cells induce dendritic cell‐mediated suppression via interferon‐γ‐induced IDO

Cited by 67 publications

References 61 publications

Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3⁺ Treg

Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3⁺ Treg

Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase

Sphingosine 1-Phosphate Receptor 3–Deficient Dendritic Cells Modulate Splenic Responses to Ischemia-Reperfusion Injury

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Apoptotic cells induce dendritic cell‐mediated suppression via interferon‐γ‐induced IDO

Cited by 67 publications

References 61 publications

Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3+ Treg

Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3+ Treg

Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase

Sphingosine 1-Phosphate Receptor 3–Deficient Dendritic Cells Modulate Splenic Responses to Ischemia-Reperfusion Injury

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Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3⁺ Treg

Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3⁺ Treg