No abstract

Antigen presentation by professional antigen‐presenting cells (pAPCs) to cytotoxic CD8+ T cells can occur via two processing routes – the direct and cross‐presentation pathways. Cross‐presentation of exogenous antigens in the context of major histocompatibility complex (MHC) class I molecules has recently attracted a lot of research interest because it may prove crucial for vaccine development. This alternative pathway has been implicated in priming CD8+ T‐cell responses to pathogens as well as tumours in vivo (cross‐priming). In cross‐presentation, the internalized antigens can be processed through diverse intracellular routes. As many unresolved questions regarding the molecular basis that controls the cross‐priming process still exist, it is essential to explore the various elements involved therein, to better elucidate this pathway. In this review, we summarize current data that explore how the source and nature of antigens could affect their cross‐presentation. Moreover, we will discuss and outline how recent advances regarding pAPCs’ properties have increased our appreciation of the complex nature of the cross‐priming pathway in vivo. In conclusion, we contemplate how the direct and cross‐presentation pathways can function to allow the immune system to deal efficiently with diverse pathogens.

The initiation of CD8 1 T cell (CTL) immune responses can occur via cross-priming. Recent data suggested a relationship between cross-presentation and immunodominance of epitope-specific T cells. To test this association, we evaluated the efficacy of crosspresentation for several virus epitopes in vitro and examined if this can be extrapolated in vivo. Employing lymphocytic choriomeningitis virus (LCMV), we demonstrate that the cross-presentation and cross-priming of LCMV antigens were dominated by NP396, but not NP205 when analyzing the LCMV-NP. Although with LCMV-GP, cross-presentation was dominated by GP276, and cross-priming was dominated by GP33. Importantly, although NP396 was significantly more efficient than GP33 in cross-presentation, cross-priming of their specific CTL was comparable. In a subsequent virus challenge after cross-priming, GP33-specific CTL dominated the response. Accordingly, based on our data, the ability of viral epitopes to be cross-presented in vitro does not entirely reflect what would occur in cross-priming. Thus, weak cross-presenting antigens may still cross-prime an efficient CTL response depending on other in vivo elements such as the naïve T-cell precursor frequencies.

Immunogenic epitopes that stimulate CD8+ T cells can be organized into an immunodominance hierarchy, based on their ability to induce T-cell priming and subsequent expansion. Cytotoxic CD8+ T cells can be primed through the cross-priming pathway, where exogenous viral proteins are acquired by professional antigen-presenting cells (pAPCs). We have previously reported that lymphocytic choriomeningitis nucleoprotein (LCMV-NP) expressed in HEK cells (HEK-NP) induces cross-priming of CD8+ T cells in vivo. In this study, we have used this HEK-NP model to study the effects of LCMV-NP cross-priming on the LCMV immunodominance hierarchy following viral challenge. Our results highlight the contribution of cross-priming to the immune response, since the T-cell hierarchy was significantly altered as a result of exogenous processing of a single virus protein, and this phenomenon was maintained throughout the memory response. Moreover, as a result of cross-priming, in vivo CD8+ T-cell killer activity was enhanced during subsequent virus assaults. These findings have significant implications for immunotherapy because they demonstrate that exogenous delivery of specific T-cell epitopes can be utilized to manipulate the host's CD8+ T-cell memory immunodominance responses.

The initiation of T-cell immune responses requires professional antigen-presenting cells. Emerging data point towards an important role for macrophages (M/) in the priming of naïve T cells. In this study we analyzed the efficiency and the mechanisms by which M/ derived from spleen (Sp-M/) or bone marrow (BM-M/) present Lymphocytic choriomeningitis virus (LCMV) antigens to epitope-specific T cells. We demonstrate that because of phagosomal maturation, Sp-M/ downregulate their ability to cross-present cell-associated, but not soluble, antigens, as they are further differentiated in culture without altering their capacity to directly present virus antigens after infection. We propose that Sp-M/ are extremely efficient at direct and cross-presentation. However, if these cells undergo further M-CSF-dependent maturation, they will adapt to be more scavenger and phagocytic and concurrently reduce their cross-presenting capacity. Accordingly, Sp-M/ can have an important role in regulating T-cell responses through cross-presentation depending on their differentiation state.