Let Me Present to You: The presentation of exogenous antigens by major histocompatibility (MHC) class I molecules is referred to as cross-presentation. Cross-presentation by dendritic cells plays a central role in the priming of cytolytic T lymphocyte responses to natural and vaccine antigens and also in the initiation of autoimmune diseases such as type 1 diabetes. A satisfactory cell biological model of cross-presentation is not available, which would be required to decipher the link, inherent in cross-presentation, between the secretory and the endocytic pathways. Saveanu et al. (p. 213 , published online 4 June) identify an aminopeptidase, insulin-regulated aminopeptidase (IRAP), which interacts directly with MHC class I molecules. IRAP plays an exclusive and important role in MHC class I cross-presentation of receptor-targeted and phagocytosed antigens. In particular, a specific endosomal compartment, which carries IRAP as a unique marker, is implicated in cross-presentation of phagocytosed antigens.

Dendritic cells have the unique ability to pick up dead cells carrying antigens in tissue and migrate to the lymph nodes where they can cross-present cell-associated antigens by MHC class I to CD8+ T cells. There is strong in vivo evidence that the mouse XCR1+ dendritic cells subset acts as a key player in this process. The intracellular processes underlying cross-presentation remain controversial and several pathways have been proposed. Indeed, a wide number of studies have addressed the cellular process of cross-presentation in vitro using a variety of sources of antigen and antigen presenting cells. Here we review the in vivo and in vitro evidence supporting the current mechanistic models and disscuss their physiological relevance to the cross-presentation of cell-associated antigens by dendritic cells subsets

Endoplasmic reticulum-associated aminopeptidase 1 (ERAP1) is involved in the final processing of endogenous peptides presented by MHC class I molecules to CTLs. We generated ERAP1-deficient mice and analyzed cytotoxic responses upon infection with three viruses, including lymphocytic choriomeningitis virus, which causes vigorous T cell activation and is controlled by CTLs. Despite pronounced effects on the presentation of selected epitopes, the in vivo cytotoxic response was altered for only one of several epitopes tested. Moreover, control of lymphocytic choriomeningitis virus was not impaired in the knockout mice. Thus, we conclude that lack of ERAP1 has little influence on antiviral immunohierarchies and antiviral immunity in the infections studied. We also focused on the role of ERAP1 in cross-presentation. We demonstrate that ERAP1 is required for efficient cross-presentation of cell-associated Ag and of OVA/anti-OVA immunocomplexes. Surprisingly, however, ERAP1 deficiency has no effect on cross-presentation of soluble OVA, suggesting that for soluble exogenous proteins, final processing may not take place in an environment containing active ERAP1.