A central process of the immune response against viruses is the MHC class I (MHC I)-mediated antigen presentation. Cellular and pathogen-derived peptides are loaded on MHC I and transported to the cell surface. The majority of MHC I-presented peptides are generated in the cytosol of the cell by the proteasome. The antigenic transporter TAP translocates cytosolic peptides into the ER, where they are loaded onto MHC I molecules (Rufer et al., 2007, J Immunol, 179, 5717-5727). Once a peptide binds, the MHC I-peptide complex leaves the ER via the Golgi apparatus and the trans-Golgi network (TGN) to the cell surface. Presentation of "non-self“ viral peptides at the cell surface triggers the elimination of the virus-infected cell by cytotoxic T-cells (CTLs) (Leonhardt, R.M. & Knittler M.R., 2003, BioSpektrum 9, 23-26).
Viruses, which are not recognized by the immune system, have an enormous selection advantage in view of replication und spreading. This is especially true for viruses that in turn cause a weak stimulus of the immune system, for example, by subliminal replication or propagation in specific organs and tissues (so-called immune privileged tissues) or viruses that have evolved mechanisms which actively interfere with the strength and efficiency of the immune response. Examples for this are known for animals and humans and cause virus propagation of high titers and subsequently massive virus excretion, which could be of epidemiological importance.
Over millions of years of coevolution with their hosts, several viral pathogens have evolved sophisticated evasion strategies to elude the MHC I-mediated antigen presentation and in many cases lifelong persistence and repeated reactivation within the host. Basically all steps of the antigen presentation are targeted. Some of the viral factors, so called VIPRs (viral proteins interfering with antigen presentation), have been identified and functionally characterized (Verweij et al., 2008, J Immunol, 181, 4894-4907, Heller et al., 2011, J Biol Chem, 286, 10983-10997). VIPRs suppress proteasomal degradation of viral proteins, enhance degradation of TAP and MHC I, block or misroute intracellular antigen transport and could even function as “mock-MHC I“. VIPRs reflect a specific adaptation of viral pathogens to the immune response of their hosts and provide important tools to analyze the mechanisms of the antigen processing in different species, e.g. human, mouse, rat and bovine.
Evasion strategies of some viruses cause suboptimal loading of MHC I in the ER and the generation of unstable MHC I-peptide complexes. Studies by our laboratory have shown that a post-ER mechanism, which depends on the catalytic activity of proprotein convertases, can rescue stable surface expression of MHC I when the formation of stable MHC I-peptide complexes in the ER is impaired (Leonhardt et al., 2005, J Immunol, 174, 5104-5114, Leonhardt et al., 2010, J Immunol, 184, 2985-2998). This suggests for the first time that cells possess a counterstrategy that undermines viral efforts to escape from antigen presentation.
In addition to viruses, bacteria also use sophisticated mechanisms that allow these pathogens to escape from cellular immune surveillance. By using the facultative intracellular bacterium Chlamydia as a model, the alternative process of antigen presentation (MHC I-cross presentation) is investigated to see whether and to what extend these pathways act as counter strategy against pathogenic immune evasion strategies. Ongoing work demonstrates for the first time that MHC I-cross presentation in cooperation with other cellular processes allows infected immune cells (e.g. dendritic cells) to preserve their capacity to activate the immune system by functional MHC I-surface expression. In particular, it seems that stress- and cell autonomous resistant-factors, which are specifically induced upon bacterial infection of dendritic cells, play a crucial role in this context.