LOX-1 as a natural IFN-α–mediated signal for apoptotic cell uptake and antigen presentation in dendritic cells

Parlato, Stefania; Romagnoli, Giulia; Spadaro, Francesca; Canini, Irene; Sirabella, Paolo; Borghi, Paola; Ramoni, Carlo; Filesi, Ilaria; Biocca, Silvia; Gabriele, Lucia; Belardelli, Filippo

doi:10.1182/blood-2009-07-234468

Cited by 72 publications

(68 citation statements)

References 48 publications

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“…Consistent with this view, studies on human DC indicate that IFN-I can affect the expression of a number of genes associated with processing as well as the expression of inducible proteasome subunits (11,27,28). It is worth mentioning that in our setting, withdrawal of apoEG7 cells from the coculture at 3 h did not prevent IFN-induced Ag retention and OVA cross-presentation in CD8a + DC, provided that IFN-I were maintained in the culture for the remaining 15 h. In fact, removal of both apoEG7 cells and IFN-I after the 3-h culture resulted in only partial Ag retention and no DC activation and cross-presented OVA (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 70%

“…Among these soluble mediators, IFN-I have been described to be particularly efficient in inducing cross-priming in a CD4 T cell-independent manner, implying a faster immune reaction (9,10). Besides the appreciated effects in promoting cross-priming against soluble or viral Ag, some recent evidence suggests that IFN-I may also affect cross-presentation of cell-associated Ag (11). Of note, a recent study on the newly described mouse merocytic DC subset has shown that these cells are endowed with potent ability to prime both CD4 and CD8 T cells against tumor cell-associated Ag partly through their ability to produce IFN-I upon engulfment of apoptotic tumor cells (32).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, cross-priming stimulated by TLR3, TLR4, and TLR9 ligands was shown to be critically dependent on IFN-I signaling, implying these cytokines as important mediators in infection-stimulated cross-priming (9). Recent work from our laboratory has shown that human DC generated in the presence of IFN-a exhibit enhanced cross-presentation of allogeneic apoptotic cell Ag to autologous CD8 T cells, suggesting a role for IFN-I in DC cross-presentation of cell-associated Ag (11). In this study, we demonstrate that IFN-I promote cross-priming in vivo against cellassociated Ag derived from tumor apoptotic cells through multiple actions on CD8a + DC, as follows: 1) by enhancing Ag persistence and, thus, cross-presentation; 2) by sustaining the survival of Agbearing DC selectively; and 3) by activating DC.…”

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confidence: 95%

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Type I IFNs Control Antigen Retention and Survival of CD8α+ Dendritic Cells after Uptake of Tumor Apoptotic Cells Leading to Cross-Priming

Lorenzi

Mattei

Sistigu

et al. 2011

The Journal of Immunology

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118

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Cross-presentation is a crucial mechanism for generating CD8 T cell responses against exogenous Ags, such as dead cell-derived Ag, and is mainly fulfilled by CD8α+ dendritic cells (DC). Apoptotic cell death occurring in steady-state conditions is largely tolerogenic, thus hampering the onset of effector CD8 T cell responses. Type I IFNs (IFN-I) have been shown to promote cross-priming of CD8 T cells against soluble or viral Ags, partly through stimulation of DC. By using UV-irradiated OVA-expressing mouse EG7 thymoma cells, we show that IFN-I promote intracellular Ag persistence in CD8α+ DC that have engulfed apoptotic EG7 cells, regulating intracellular pH, thus enhancing cross-presentation of apoptotic EG7-derived OVA Ag by CD8α+ DC. Notably, IFN-I also sustain the survival of Ag-bearing CD8α+ DC by selective upmodulation of antiapoptotic genes and stimulate the activation of cross-presenting DC. The ensemble of these effects results in the induction of CD8 T cell effector response in vitro and in vivo. Overall, our data indicate that IFN-I cross-prime CD8 T cells against apoptotic cell-derived Ag both by licensing DC and by enhancing cross-presentation.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

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confidence: 95%

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Type I IFNs Control Antigen Retention and Survival of CD8α+ Dendritic Cells after Uptake of Tumor Apoptotic Cells Leading to Cross-Priming

Lorenzi

Mattei

Sistigu

et al. 2011

The Journal of Immunology

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118

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“…on May 12, 2018. by guest www.bloodjournal.org From cross-priming of IFN-␥-secreting CD8 ϩ T cells 46 and also prime a Th17 response against apoptotic cell-derived Ags, 44 as well as on the results of the present study, it can be assumed that IFN-DCs injected into dying tissues can take up apoptotic cell-derived material, efficiently process tumor-associated Ags, including selfAgs, and prime both Th1 and Th17 responses, thereby leading to the expansion and activation of tumor-reactive effector T cells.…”

Section: Discussionmentioning

confidence: 99%

IFN-α enhances cross-presentation in human dendritic cells by modulating antigen survival, endocytic routing, and processing

Spadaro

Lapenta

Donati

et al. 2012

Blood

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IntroductionOver the past years, it has become apparent that type-I interferons (IFNs) affect adaptive immunity through their effects on monocytes. In particular, IFN-␣ has been shown to act as a potent inducer of the rapid differentiation of human monocytes into highly activated and partially mature dendritic cells (DCs), known as IFN-DCs. 1 We demonstrated previously that human monocytes exposed to granulocyte macrophage colony-stimulating factor (GM-CSF) and IFN-␣ are rapidly induced to express a set of membrane molecules involved in antigen (Ag) presentation and T-cell costimulation, as well as to strongly promote T helper (Th)-1 response and CD8 ϩ T cell cross-priming. 2 Moreover, IFN-DCs were shown to cross-present very efficiently low amounts of nonstructural-3 protein (NS3) of hepatitis C virus (HCV) to a specific CD8 ϩ T cell clone, even in the absence of CD4 ϩ T-cell help. 2 The cross-presentation efficiency of DCs is not dictated solely by their Ag capture capability 3 ; it also is affected by critical factors such as (1) the route of Ag uptake, (2) acidification-sensitive Ag degradation in endosomal-lysosomal compartments, and (3) Ag entry into the major histocompatibility complex class-I (MHC-I) pathway. [4][5][6][7][8] At present, 4 nonmutually exclusive models have been proposed to explain cross-presentation. [8][9][10] In the canonical cytosolic pathway, endocytosed Ags are translocated into the cytosol, where they are degraded by the proteasome, and then the antigenic peptides are transported into the lumen of the endoplasmic reticulum (ER) by the transporters associated with Ag processing (TAPs), 9,10 or alternatively, reimported from the cytoplasm into the early endosomes and loaded onto endosomal 12 According to a less well-defined TAP-and proteasomeindependent endosomal pathway, Ags can be processed by endosomal proteases and loaded onto MHC-I molecules directly within early and late endosomes and lysosomes. [13][14][15] An additional model involves the delivery of components of the ER to endocytic organelles or the transport of incoming Ags to the ER. [16][17][18] Here, we have investigated the mechanisms underlying the superior efficiency of IFN-DCs in the cross-presentation of soluble proteins, by studying (1) the Ag uptake and trafficking to the class-I processing pathway, (2) the maturation kinetic of the organelles containing the internalized proteins, (3) the Ag stability within endosomes, and (4) the Ag processing and cross-presentation to specific CD8 ϩ T cells. The results reveal that IFN-DCs exhibit a delayed endosomal acidification associated with a prolonged Ag survival and retention in the early endosomal compartment, as well as with Ag trafficking to recycling pathways. In IFN-DCs, both early and recycling endosomal compartments serve as important stores of MHC-I molecules, allowing rapid presentation of exogenous Ags. These findings provide novel mechanistic insight into the cross-presentation efficiency of IFN-DCs and underscore the potential advantage of using these cellula...

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“…We described a new class of highly active monocyte-derived dendritic cells generated in the presence of IFN-a and GM-CSF (IFN-DC) within three days, in the absence of maturation factors and without the need for extensive operations or manipulations (7). Although IFN-DC exhibit some features of mature DC, including the ability to promote the efficient cross-priming of CD8 + cells (7)(8)(9)(10)(11), they also retain the capacity to efficiently engulf proteins and apoptotic cells. In contrast to conventional DC (IL-4-DC), IFN-DC are fully able to preserve internalized proteins from early degradation and to route Ag to the MHC class I-processing pathway, allowing long-lasting Ag presentation (9,11).…”

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NK Cell Activation in the Antitumor Response Induced by IFN-α Dendritic Cells Loaded with Apoptotic Cells from Follicular Lymphoma Patients

Lapenta

Donati

Spadaro

et al. 2016

The Journal of Immunology

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Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma. This malignancy is considered virtually incurable, with high response rates to therapy but frequent relapses. We investigated the ability of monocyte-derived dendritic cells generated in the presence of IFN-α and GM-CSF (IFN-DC) and loaded with apoptotic lymphoma cells to activate immune responses against FL cells, with the ultimate goal of designing novel patient-specific vaccination strategies for the treatment of FL. In this article, we show that apoptotic tumor cell–loaded IFN-DC from FL patients, which were cultured for 2 wk with autologous lymphocytes, led to Th1 response skewing, based on significantly higher levels of IFN-γ production and a remarkable increase in CD8+ and NK cell frequency, consistent with the detection of enhanced cytotoxic effector function toward autologous FL cells. IFN-DC were found to promote efficient NK cell activation, increased expression of cytotoxicity receptors, and extensive IFN-γ production in the virtual absence of IL-10. Moreover, direct recognition and killing of primary autologous lymphoma cells by activated NK cells from FL patients was also demonstrated. A critical role was demonstrated for MHC class I–related chain A and B and membrane-bound IL-15 in IFN-DC–mediated NK cell activation and early IFN-γ production. The overall results indicate that IFN-DC loaded with autologous apoptotic FL cells represent a valuable tool for improving the potency of therapeutic cancer vaccines through the efficient induction of NK cell activation and promotion of CD8+ T cell antitumor immunity.

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LOX-1 as a natural IFN-α–mediated signal for apoptotic cell uptake and antigen presentation in dendritic cells

Cited by 72 publications

References 48 publications

Type I IFNs Control Antigen Retention and Survival of CD8α+ Dendritic Cells after Uptake of Tumor Apoptotic Cells Leading to Cross-Priming

Type I IFNs Control Antigen Retention and Survival of CD8α+ Dendritic Cells after Uptake of Tumor Apoptotic Cells Leading to Cross-Priming

IFN-α enhances cross-presentation in human dendritic cells by modulating antigen survival, endocytic routing, and processing

NK Cell Activation in the Antitumor Response Induced by IFN-α Dendritic Cells Loaded with Apoptotic Cells from Follicular Lymphoma Patients

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