Role of Immunoproteasomes in Cross-Presentation

Abstract

The evidence that proteasomes are involved in the processing of cross-presented proteins is indirect and based on the in vitro use of proteasome inhibitors. It remains, therefore, unclear whether cross-presentation of MHC class I peptide epitopes can occur entirely within phagolysosomes or whether it requires proteasome degradation. To address this question, we studied in vivo cross-presentation of an immunoproteasome-dependent epitope. First, we demonstrated that generation of the immunodominant HY Uty246–254 epitope is LMP7 dependent, resulting in the lack of rejection of male LMP7-deficient (LMP7−/−) skin grafts by female LMP7−/− mice. Second, we ruled out an altered Uty246–254-specific T cell repertoire in LMP7−/− female mice and demonstrated efficient Uty246–254 presentation by re-expressing LMP7 in male LMP7−/− cells. Finally, we observed that LMP7 expression significantly enhanced cross-priming of Uty246–254-specific T cells in vivo. The observations that male skin grafts are not rejected by LMP7−/− female mice and that presentation of a proteasome-dependent peptide is not efficiently rescued by alternative cross-presentation pathways provide strong evidence that proteasomes play an important role in cross-priming events.

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

“…Immunoproteasomes, which have been implicated in cross-presentation [23], could also account for GP276 poor cross-presentation since it can downregulate GP276 presentation [24]. We have detected LMP7 expression in DC2.4 (unpublished data), which concurs with the previous data showing that immunoproteasomes are expressed in DC irrespective of their maturation states [25].…”

Why the Structure but Not the Activity of the Immunoproteasome Subunit Low Molecular Mass Polypeptide 2 Rescues Antigen Presentation

“…When we analyzed the presentation of the endogenously expressed male minor Ag UTY on mouse splenocytes, we observed that the epitope is not only LMP7 dependent, as previously reported (14,33), but also dependent on LMP2 (Figs. 1A, 2E).…”

“…The HY-Ag-derived MHC-I epitope UTY 246-254 is LMP7 and LMP2 dependent Generation of the CTL epitope UTY 246-254 (ubiquitously transcribed tetratricopeptide repeat gene, Y-linked), derived from the endogenously expressed Y-chromosome-encoded HY-Ag, has been demonstrated to be LMP7 dependent (14,33). To confirm this result and to investigate whether the other immunoproteasome subunits LMP2 and MECL-1 were similarly affecting this epitope, UTY 246-254 presentation on the H-2D b class I molecule of malederived splenocytes was determined with a UTY 246-254 -specific T cell hybridoma in lacZ assays (Fig.…”

Selective suicide of cross-presenting CD8 + dendritic cells by cytochrome c injection shows functional heterogeneity within this subset

“…1 d and e). A major conclusion from our work is that only a subset of CD8 ϩ DCs possesses a highly efficient mechanism for endosome-to-cytosol transport [where access to the TAP/proteasome pathway is gained (5)] that makes it particularly specialized at cross-presentation of exogenous Ag.…”

“…There is evidence to suggest that the specialized ability of DCs for cross-presentation may be explained in part by the presence of a unique, size-selective intracellular pathway for export of Ag from endosomal compartments into the cytosol for access to the conventional MHC class I processing pathway (2), although this has not specifically been shown for the CD8 ϩ DC subset. Recent data also suggest that the cytosolic crosspresentation pathway is the major relevant mechanism in vivo (5) and that the machinery that confers cross-presentation specialization is located downstream from Ag uptake (6). Despite the progress in our understanding of the mechanisms of crosspresentation, in vivo application of cross-presentation to manipulate (enhance or reduce) a CD8 ϩ T cell response remains to be exploited.…”