Dataset Information

Dendritic cell maturation in HCV infection: altered regulation of MHC class I antigen processing-presenting machinery.

ABSTRACT:

Background & aims

Modulation of dendritic cell (DC) function has been theorized as one of the mechanisms used by hepatitis C virus (HCV) to evade the host immune response and cause persistent infection.

Methods

We used a range of cell and molecular biology techniques to study DC subsets from uninfected and HCV-infected individuals.

Results

We found that patients with persistent HCV infection have lower numbers of circulating myeloid DC and plasmacytoid DC than healthy controls or patients who spontaneously recovered from HCV infection. Nonetheless, DC from patients with persistent HCV infection display normal phagocytic activity, typical expression of the class I and II HLA and co-stimulatory molecules, and conventional cytokine production when stimulated to mature in vitro. In contrast, they do not display the strong switch from immunoproteasome to standard proteasome subunit expression and the upregulation of the transporter-associated proteins following stimulation, which were instead observed in DC from uninfected individuals. This different modulation of components of the HLA class I antigen processing-presenting machinery results in a differential ability to present a CD8(+) T cell epitope whose generation is dependent on the LMP7 immunoproteasome subunit.

Conclusions

Overall, these findings establish that under conditions of persistent HCV antigenemia, HLA class I antigen processing and presentation are distinctively regulated during DC maturation.

SUBMITTER: Leone P

PROVIDER: S-EPMC8759579 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The well described conventional antigen-processing pathway is accountable for most peptides that end up in MHC class I molecules at the cell surface. These peptides experienced liberation by the proteasome and transport by the peptide transporter TAP. However, there are multiple roads that lead to Rome, illustrated by the increasing number of alternative processing pathways that have been reported during last years. Interestingly, TAP-deficient individuals do not succumb to viral infections, suggesting that CD8 T cell immunity is sufficiently supported by alternative TAP-independent processing pathways. To date, a diversity of viral and endogenous TAP-independent peptides have been identified in the grooves of different MHC class I alleles. Some of these peptides are not displayed by normal TAP-positive cells and we therefore called them TEIPP, for "T-cell epitopes associated with impaired peptide processing." TEIPPs are hidden self-antigens, are derived from normal housekeeping proteins, and are processed via unconventional processing pathways. Per definition, TEIPPs are presented via TAP-independent pathways, but recent data suggest that part of this repertoire still depend on proteasome and metalloprotease activity. An exception is the C-terminal peptide of the endoplasmic reticulum (ER)-membrane-spanning ceramide synthase Trh4 that is surprisingly liberated by the signal peptide peptidase (SPP), the proteolytic enzyme involved in cleaving leader sequences. The intramembrane cleaving SPP is thereby an important contributor of TAP-independent peptides. Its family members, like the Alzheimer's related presenilins, might contribute as well, according to our preliminary data. Finally, alternative peptide routing is an emerging field and includes processes like the unfolded protein response, the ER-associated degradation, and autophagy-associated vesicular pathways. These data convince us that there is a world to be discovered in the field of unconventional antigen processing.