SummaryThe immunostimulating complex or 'iscom' was first described 20 years ago as an antigen delivery system with powerful immunostimulating activity. Iscoms are cage-like structures, typically 40 nm in diameter, that are comprised of antigen, cholesterol, phospholipid and saponin. ISCOM TM -based vaccines have been shown to promote both antibody and cellular immune responses in a variety of experimental animal models. This review focuses on the evaluation of ISCOM TM -based vaccines in animals over the past 10 years, as well as examining the progress that has been achieved in the development of human vaccines based on ISCOM TM adjuvant technology.

Primary CD8+ T cell (TCD8+) responses to viruses are directed toward multiple Ags and shaped by both the level of Ag presentation and the underlying Ag-specific TCD8+ repertoire. The relative importance of these factors in deciding the hierarchy of TCD8+ responses and how they are influenced by the immunoproteasome are not well understood. Using an influenza infection model in mice deficient in various immunoproteasome subunits, we observe that Ag presentation and TCD8+ repertoire are altered in an epitope-specific and immunoproteasome subunit-dependent manner. More importantly, we find that the level of Ag presentation and the extent of the underlying repertoire can work either alone or in concert to determine definitively the magnitude of the individual TCD8+ responses and hence the overall TCD8+ hierarchy. Together, these results provide a clearer understanding of how immunodominance hierarchies are established.

T cell responses are characterized by the phenomenon of immunodominance (ID), whereby peptide-specific T cells are elicited in a reproducible hierarchy of dominant and subdominant responses. However, the mechanisms that give rise to ID are not well understood. We investigated the effect of viral dose on primary CD8+ T cell (TCD8+) ID by injecting mice i.p. with various doses of influenza A virus and assessing the primary TCD8+ response to five dominant and subdominant peptides. Increasing viral dose enhanced the overall strength of the TCD8+ response, and it altered the ID hierarchy: specifically, NP366–374 TCD8+ were dominant at low viral doses but were supplanted by PA224–233 TCD8+ at high doses. To understand the basis for this reversal, we mathematically modeled these TCD8+ responses and used Bayesian statistics to obtain estimates for Ag presentation, TCD8+ precursor numbers, and avidity. Interestingly, at low viral doses, Ag presentation most critically shaped ID hierarchy, enabling TCD8+ specific to the more abundantly presented NP366–374 to dominate. By comparison, at high viral doses, TCD8+ avidity and precursor numbers appeared to be the major influences on ID hierarchy, resulting in PA224–233 TCD8+ usurping NP366–374 cells as the result of higher avidity and precursor numbers. These results demonstrate that the nature of primary TCD8+ responses to influenza A virus is highly influenced by Ag dose, which, in turn, determines the relative importance of Ag presentation, TCD8+ avidity, and precursor numbers in shaping the ID hierarchy. These findings provide valuable insights for future TCD8+-based vaccination strategies.