Dendritic Cell Aggresome-Like-Induced Structure Formation and Delayed Antigen Presentation Coincide in Influenza Virus-Infected Dendritic Cells

Abstract

Influenza virus infection induces maturation of murine dendritic cells (DCs), which is most important for the initiation of an immune response. However, in contrast to EL-4 and MC57 cells, DCs present viral CTL epitopes with a delay of up to 10 h. This delay in Ag presentation coincides with the up-regulation of MHC class I molecules as well as costimulatory molecules on the cell surface and the accumulation of newly synthesized ubiquitinated proteins in large cytosolic structures, called DC aggresome-like-induced structures (DALIS). These structures were observed previously after LPS-induced maturation of DCs, and it was speculated that they play a role in the regulation of MHC class I Ag presentation. Our findings provide the first evidence for a connection between DC maturation, MHC class I-restricted Ag presentation, and DALIS formation, which is further supported by the observation that DALIS contain ubiquitinated influenza nucleoprotein.

Antigen‐presentation capacity of dendritic cells is impaired in ongoing enterovirus myocarditis

“…3C). In agreement with data showing an association between DRiPs, DALIS formation and antigenic processing in influenza virus infection [29], these findings indicate the presence of a CVB3 protein-containing DRiP pool that is trapped in DALISs during DC maturation in CVB3 infection in A.BY/SnJ mice. In addition to severe maturation/DC activation defects in CVB3-challenged A.BY/SnJ mice, limitation of the CVB3-protein containing antigenic pool may further impair T-cell priming in this host.…”

“…3A and B). Thus, once optimal expression levels of cytokines/chemokines, MHC molecules and co-stimulatory molecules were achieved in C57BL/6 mice, DALISs were dissolved presumably resulting in MHC-I antigen processing by the proteasome [4,29,31]. In contrast to the findings in the resistant host, DALIS maintenance was detected in DCs from A.BY/SnJ mice also at later stages of maturation (high detection levels at 48 h p.i.…”

“…In addition to the aforementioned exogenous route of partially proteasome-dependent antigen processing in DCs, MHC-I antigen processing of endogenous proteins from defective ribosomal products (DRiPs) [26,27] is tightly coordinated within DC maturation as well: DRiPs transiently accumulate as polyubiquitinylated conglomerates in DALISs during DC maturation [ 28,29]. To study this process in the murine model of ongoing enterovirus myocarditis, poly-ubiquitinylation and DALIS formation were assessed in DCs from both C57BL/6 and A.BY/SnJ mice.…”

“…20S and 26S proteasome activity were not affected within DC maturation in both hosts (data not shown). DALISs are dedicated areas of antigen storage, allowing for the prioritized degradation of proteins during infection [28,29] until the secretion of proinflammatory cytokines and expression of co-stimulatory molecules has been induced in mature DCs [29]. Impaired degradation of DALISs in A.BY/SnJ mice may point to a limitation of the endogenous DRiP supply for MHC-I restricted antigen processing due to prolonged storage of DRiPs in DALISs.…”

Correlation of dendritic cell maturation and the formation of aggregates of poly-ubiquitinated proteins in the cytosol

“…In line with this hypothesis it has been shown that the presentation of, e.g. the immunodominant inXuenza virus nucleoprotein (NP)-derived CTL epitope is delayed in BMDCs compared to non-professional APCs [5], and this delay coincides with the formation of DALIS.…”