It has been generally accepted as a rule that peptides binding to MHC class I molecules are derived from proteins synthesized within the cell, including peptides of genuine cellular origin as well as those encoded by viruses or other intracellular infectious agents. In contrast, MHC class II molecules, in general, bind peptides derived from exogenous proteins that have been processed via phago-lysozomes and replace the invariant chain clip fragment associated with class II molecules [1, 2]. MHC class I restriction correlates with CD8+ cytotoxic T cells (CTL) and class II restriction with CD4+ T (Th) cells. However, soon after the initial formulation of these general rules, differential MHC restriction as well as the division of labor between endogenous versus exogenous loading of MHC class I and class II molecules were questioned [3–13]. The subject of this editorial is so-called “cross-presentation” and “cross-priming” as well as “cross-tolerance”, which may be defined as the presentation of exogenous antigen via MHC class I for generating stimulatory or tolerogenic responses in CD8+ T cells, respectively (Table 1)[10]; accordingly, exogenous antigen has “crossed” over to the endogenous pathway to gain access to MHC class I. The use of the term “crosspriming” for peptides presented on MHC class II molecules is not warranted because this is the conventional pathway for class II presentation (eg [14]). Recently, MHC class I-specific presentation of exogenous antigen to induce cross-priming, cross-presentation, or crosstolerance has become viewed by many as a general and important phenomenon [5, 9, 10, 13, 15]. This emerging view is based on the concept that activation of CD4+ Th cells or CD8+ T CTL requires antigen (signal 1) plus costimulation (signal 2), whereas encounters with signal 1 alone result in anergy or deletion [16–19]. This was the basis for the proposal: Unless cross-presentation plays an essential role, self-encoded antigens, which are extralymphatic, could not render T cells tolerant, and viruses, which do not infect professional antigenpresenting cells (APC, expressing both antigen as signal 1 and signal 2) or tumor cells (that do not express signal 2) could not elicit MHC class I-restricted CTL [5, 9, 10, 13].

In biology, particularly in immunology, nothing is impossible. However, as a result of co-evolution of pathogens and their hosts, there has been selection of frequent or likely pathways and effector mechanisms against unlikely rare forms and exceptions. Therefore, the key question here is: Is cross-priming via MHC class I a general and essential characteristic of physiologically important CD8+ CTL cytolytic or tolerogenic responses or, alternatively, is this process an exception that, perhaps under special conditions, can be exploited therapeutically to induce responses that otherwise would be difficult to generate (Table 1)?