Department of Immunochemistry

Our department analyzes how pathogens such as viruses acquire the ability to evade the immune system and how host immune systems have acquired resistance to various pathogens. In particular, we are studying a fundamental host defense mechanism that acts against various pathogens by employing various immune regulatory receptors. Of particular interest are the ‘paired receptors’ that are expressed on various immune cells and consist of activating and inhibitory receptors (Figure 1). Our identification of the host ligands and viral ligands that these paired receptors recognize has led us to propose that these paired receptors have evolved in tandem with pathogens. In addition, we have found that these receptors are also involved in viral entry into cells. These studies will help to elucidate the fundamental mechanisms by which pathogens evade the host immune system and the host factors that shape resistance to various infections. This research will help to build the foundation that is required for the development of new vaccines and therapies for infectious diseases.

(1) Analysis of the ligands recognized by ‘paired receptors’ and the consequences of recognition.
Immune cells express various receptor pairs that consist of activating and inhibitory receptors that are highly homologous to each other. The inhibitory receptors recognize self-antigens such as MHC molecules. In contrast, the activating receptors generally do not recognize self-antigens and their ligands remain unclear at present. We have found that one of these paired receptors recognizes cytomegalovirus protein and we showed that paired receptors play an important role in determining host resistance to pathogens (Figure 2). We are continuing to analyze the functions of these receptors to elucidate the interactions between pathogens and the host immune system.

Figure 1. Paired receptors Paired receptors consist of inhibitory and activating receptors that are highly homologous to each other. The inhibitory receptors transduce inhibitory signal via ITIM in their cytoplasmic domain whereas the activating receptors transduce activating signals by associating with ITAM-bearing adaptor molecules.

Figure 2. Recognition of cytomegalovirus-infected cells by inhibitory and activating paired receptors Viruses have acquired MHC-like molecules that serve as ligands for inhibitory receptors expressed on the NK cells of susceptible mice strains. As a result, virus-infected cells are not killed by NK cells, even though they express MHC at low levels (left). In contrast, NK cells from resistant mouse strains do not express inhibitory receptors that recognize virus MHC-like molecules. Instead, they express activating receptors that do recognize virus MHC-like molecules; therefore, these cells can effciently eliminate virus-infected cells (right) (Arase et al. Science 2002).

(2) Mechanisms by which viruses enter cells.
Several viruses that show persistent infection downregulate immune responses by expressing ligands that are recognized by inhibitory receptors. Interestingly, we have found that some viruses also exploit these inhibitory receptors to enter the cell. For example, such an interaction between immune receptors and viral proteins is involved in the entry mechanism of herpes simplex virus (HSV) and varicella-zoster virus (VZV) (Figure 3). Since other viruses may also use similar receptors to enter cells, we are continuing to investigate the molecular mechanisms by which viruses enter cells.

Figure 3. Mechanism by which viruses enter cells
Some viruses express ligands for inhibitory receptors and downregulate the immune response. We found that PILRα, the inhibitory member of a receptor pair, recognizes herpes simplex virus (HSV)-infected cells. Molecular cloning of the ligands for PILRα revealed that PILRα associates with HSV glycoprotein B, which plays an essential role in HSV infection. Furthermore, the interaction between PILRα and glycoprotein B was found to be involved in the entry of the virus into cells. We also found that glycoprotein B of varicella-zoster virus (VZV) associates with myelin-associated glycoprotein (MAG, Siglec-4), one of paired receptors, and that this association mediates the cell entry of VZV. Thus, paired receptors play important roles in both immune regulation and the host cell entry of viruses.