IFN-α boosts epitope cross-presentation by dendritic cells via modulation of proteasome activity

Lattanzi, Laura; Rozera, Carmela; Marescotti, Diego; D’Agostino, Giuseppina; Santodonato, Laura; Cellini, Silvia; Belardelli, Filippo; Gavioli, Riccardo; Ferrantini, Maria

doi:10.1016/j.imbio.2010.10.003

Cited by 45 publications

(33 citation statements)

References 57 publications

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“…In line with the direct activation/inhibition relationship between IFNγ and PSMB8 depicted in network 3 (see Supplementary data file 3) and the previously referred reports [39,41], we found out that the highest levels of PSMB8 in tissue is coinciding with the increase of IFNγ mRNA at 2 dpi. Since proteasomal activity is dependent on the ubiquitination of its targets [41], the significant enrichment of the "Protein ubiquitination pathway" uncovered by IPA analysis gives an additional evidence of the enhancement of protein degradation by immunoproteasome as a result of infection.…”

Section: Discussionsupporting

confidence: 89%

“…Otherwise, presentation of exogenous antigens has been classically attributed to MHC class II [40]. Additionally, the term cross-presentation was introduced as an alternative mechanism to define a process in which antigens acquired from the extracellular environment are present by antigen-presenting cells (APCs) to CD8+ T cells via their own MHC-I molecules [41]. Interestingly, this mechanism could explain the clear indications of adaptive immunity induction via MHC-I which is derived from the proteomic results obtained in our work.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Proteomic analysis of porcine mesenteric lymph-nodes after Salmonella typhimurium infection

Martins¹,

Collado-Romero²,

Martínez-Gomáriz³

et al. 2012

Journal of Proteomics

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Proteomic analysis of porcine mesenteric lymph-nodes after Salmonella typhimurium infection

Martins¹,

Collado-Romero²,

Martínez-Gomáriz³

et al. 2012

Journal of Proteomics

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“…In contrast, matured DCs showed decreased proteasomal activities upon maturation with a 30% lower caspase-like activity, and a 40% to 50% lower tryptic activity in LPS- and R848-matured DCs. In DCs caspase-like, tryptic, and chymotryptic hydrolytic activities inversely correlated with the expression of maturation markers CD83 + and CD86 + after LPS- or R848-induced maturation (rs=-0.4191, p=0.042; rs=-0.4200, p=0.029; and rs=-0.6018, p=0.002, respectively), which supports decreased proteasomal activities upon maturation of DCs (Figure 1D), as demonstrated by others in IFN-treated human primary DCs (44). To assess how TLR stimulation changes protease activities in maturing DCs, we measured proteasomal and aminopeptidases activities at 5h, 24h, and 48h post stimulation with LPS or CL097 and calculated a ratio of activities in maturing cells over their immature counterpart at each time point (Figure 1E and Supplemental figure 2D).…”

Section: Resultssupporting

confidence: 81%

Different Antigen-Processing Activities in Dendritic Cells, Macrophages, and Monocytes Lead to Uneven Production of HIV Epitopes and Affect CTL Recognition

Dinter

Gourdain

Lai

et al. 2014

The Journal of Immunology

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Dendritic cells (DCs), macrophages (MPs) and monocytes are permissive to HIV. Whether they similarly process and present HIV epitopes to HIV-specific CD8 T cells is unknown despite the critical role of peptide processing and presentation for recognition and clearance of infected cells. Cytosolic peptidases degrade endogenous proteins originating from self or pathogens, exogenous antigens preprocessed in endolysosomes, thus shaping the peptidome available for endoplasmic reticulum (ER) translocation, trimming and MHC-I presentation. Here we compared the capacity of DCs, MPs and monocyte cytosolic extracts to produce epitope precursors and epitopes. We showed differences in the proteolytic activities and expression levels of cytosolic proteases between monocyte-derived DCs and MPs and upon maturation with LPS, R848 and CL097, with mature MPs having the highest activities. Using cytosol as a source of proteases to degrade epitope-containing HIV peptides, we showed by mass spectrometry that the degradation patterns of long peptides and the kinetics and amount of antigenic peptides produced differed among DCs, MPs and monocytes. Additionally, variable intracellular stability of HIV peptides prior to loading onto MHC may accentuate the differences in epitope availability for presentation by MHC-I between these subsets. Differences in peptide degradation led to 2- to 25-fold differences in the CTL responses elicited by the degradation peptides generated in DCs, MPs and monocytes. Differences in antigen processing activities between these subsets might lead to variations in the timing and efficiency of recognition of HIV-infected cells by CTLs and contribute to the unequal capacity of HIV-specific CTLs to control viral load.

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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%

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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IFN-α boosts epitope cross-presentation by dendritic cells via modulation of proteasome activity

Cited by 45 publications

References 57 publications

Proteomic analysis of porcine mesenteric lymph-nodes after Salmonella typhimurium infection

Proteomic analysis of porcine mesenteric lymph-nodes after Salmonella typhimurium infection

Different Antigen-Processing Activities in Dendritic Cells, Macrophages, and Monocytes Lead to Uneven Production of HIV Epitopes and Affect CTL Recognition

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

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