Glycoprotein B (gB) is one of the essential components for infection by herpes simplex virus-1 (HSV-1). Although several cellular receptors that associate with glycoprotein D (gD), such as herpes virus entry mediator (HVEM) and Nectin-1, have been identified, specific molecules that mediate HSV-1 infection by associating with gB have not been elucidated. Here, we found that paired immunoglobulin-like type 2 receptor (PILR) alpha associates with gB, and cells transduced with PILRalpha become susceptible to HSV-1 infection. Furthermore, HSV-1 infection of human primary cells expressing both HVEM and PILRalpha was blocked by either anti-PILRalpha or anti-HVEM antibody. Our results demonstrate that cellular receptors for both gB and gD are required for HSV-1 infection and that PILRalpha plays an important role in HSV-1 infection as a coreceptor that associates with gB. These findings uncover a crucial aspect of the mechanism underlying HSV-1 infection.

Antibodies against the receptor-binding-domain of the SARS-CoV-2 spike protein prevent SARS-CoV-2 infection. However, the effects of antibodies against other spike protein domains are largely unknown. Here, we screened a series of anti-spike monoclonal antibodies from COVID-19 patients, and found that some of antibodies against the N-terminal-domain (NTD) induced the open conformation of receptor binding domain (RBD) and thus enhanced the binding capacity of the spike protein to ACE2 and infectivity of SARS-CoV-2. Mutational analysis revealed that all the infectivity-enhancing antibodies recognized a specific site on the NTD. Structural analysis demonstrated that all the infectivity-enhancing antibodies bound to NTD in a similar manner. The antibodies against this infectivity-enhancing site were detected at high levels in severe patients. Moreover, we identified antibodies against the infectivity-enhancing site in uninfected donors, albeit at a lower frequency. These findings demonstrate that not only neutralizing antibodies but also enhancing antibodies are produced during SARS-CoV-2 infection.

SummaryNatural killer (NK) cells play an important role in immune response by producing interferon ~/ (IFN-~/) as well as exhibiting cytotoxic function. IFN-~/produced by NK cells has been suggested to be involved in differentiation of T helper cells. On the other hand, the NKR-P1 molecule was recently identified as one of the important NK cell receptors, and it recognizes certain kinds of oligosaccharides on target cells and triggers NK cells for cytotoxicity. In the present study, we found that NK cells produce great amounts of IFN-~/upon cross-linking of the NKR-P1 molecule. In contrast, stimulation of NK cells with IL-2 induced proliferation without producing IFN-% Similar to NK cells, NKI.1 + T cells also produced IFN-~/ upon NKR-P1 cross-linking. NKI.1 § T cells produced IFN-~/but not interleukin 4 (IL-4) upon NKtk-P1 cross-linking, whereas they secreted both IFN-~/ and IL-4 upon T cell receptor cross-linking. These results indicate that NKR-P1 is a receptor molecule on NK and NKI.1 + T cells that induces not only cytotoxicity but also IFN-~/production. Our findings provide a new pathway for IFN-~/production by NK and NKI.1 § T cells through NKR-P1 molecules; it may be essential for immune regulation.

Immune complex-mediated inflammation is a common mechanism of various autoimmune diseases. Glomerulonephritis (GN) is one of these diseases, and the main mechanism of the induction of GN has been unclear. We examined the contribution of Fc receptors in the induction of nephrotoxic GN by establishing and analyzing mice deficient in the Fc receptor ␥ chain (FcR ␥ ). Whereas all wild-type mice died from severe glomerulonephritis with hypernitremia by administration of anti-glomerular basement membrane (GBM) antibodies, all FcR ␥ -deficient mice survived. Histologically, wild-type mice showed glomerular hypercellularity and thrombotic changes, whereas the renal tissue in FcR ␥ -deficient mice was almost intact. Deposition of anti-GBM antibody as well as complement components in the GBM were equally observed in both wild-type and knockout mice. These results demonstrate that the triggering of this type of glomerulonephritis is completely dependent on

CD4+8- or CD4-8+ thymocytes have been regarded as direct progenitors of peripheral T cells. However, recently, we have found a novel NK1.1+ subpopulation with skewed T cell antigen receptor (TcR) V beta family among heat-stable antigen negative (HSA-) CD4+8- thymocytes. In the present study, we show that these NK1.1+ CD4+8- thymocytes, which represent a different lineage from the major NK1.1- CD4+8- thymocytes or CD4+ lymph node T cells, vigorously secrete interleukin (IL)-4 and interferon (IFN)-gamma upon stimulation with immobilized anti-TcR-alpha beta antibody. On the other hand, neither NK1.1- CD4+8- thymocytes nor CD4+ lymph node T cells produced substantial amounts of these lymphokines. A similar pattern of lymphokine secretion was observed with the NK1.1+ CD4+T cells obtained from bone marrow. The present findings elucidate the recent observations that HSA- CD4+8- thymocytes secrete a variety of lymphokines including IFN-gamma, IL-4, IL-5 and IL-10 before the CD4+8- thymocytes are exported from thymus. Our evidence indicates that NK1.1+ CD4+8- thymocytes are totally responsible for the specific lymphokine secretions observed in the HSA- CD4+8- thymocytes.

(1) and is expressed on immature thymocytes, activated T cells, and nonlymphoid cells in liver, ovary, and heart, etc. (2, 3). It is interesting that the loss of its expression or of its ligand results in immune disorders including autoantibody production and abnormal T cell accumulation in lymphoid organs as observed in llor orgld mice, respectively (4, 5). This indicates that the Fas and Fas ligand interaction is important for the immune system and is involved in negative selection in lymphocyte differentiation. Therefore, identification of cells that express. Fas ligand and that kill cells expressing Fas in each tissue is crucial for darifying the function of Fas in the immune system. Recently, Fas ligand was found to be expressed on activated T cells or some T cell lines (6-12). Furthermore, we have found that Fas ligand is expressed on freshly isolated NKI.1 + TCRo~/B + T cells in thymus and mediates cytotoxicity against CD4 § CD8 § thymocytes via Fas (13). However, it is still unclear whether the expression of Fas ligand is limited to the T cell population. In the present study, by analyzing highly purified NK cells, we found that NK cells express Fas ligand on the cell surface and exhibit Fas-mediated cytotoxicity against Fas-expressing target ceils. These findings suggest that NK cells may regulate the immune system through cytotoxicity against Fas-expressing ceils. Materials and MethodsMice. MRL/Mpj-+/+ (MILL +/+) and MRL/Mpj-lpr/lpr (MRL Ipr/Ipr ) mice were obtained from the Shizuoka Laboratory Animal Corporation (Hamamatsu, Shizuoka Prefecture, Japan). C57BL/6J Jcl (B6) mice were obtained from the Japan Clea Animal Corporation (Tokyo, Japan).CellPrepamtion. Cells were purified as previously described (13).Briefly, splenocytes from 6-8-wk-old B6 mice were treated with magnetic beads (Advanced Magnetics, Inc., Cambridge, MA) coupled with goat anti-mouse-IgG Ab (Cappel, Organon Teknika Co., West Chester, PA) to remove surface Ig (sIg) § B cells. The sIgsplenocytes, >90% being CD3 + cells, were used as the T cell population. To isolate NK cells, the sIg-splenocytes were mixed with anti-CD4 mAb (GK1.5) and anti-CD8 mAb (53.6.7) followed by incubation with magnetic beads coupled with goat anti-rat IgG Ab (Cappel) to enrich NK cells. The residual cells were then incubated with PE-anti-NKl

In the present report we describe a CD4+8-heat stable antigen-negative (HSA-)

Natural killer (NK) cells exhibit cytotoxicity against variety of tumor cells and virus-infected cells without prior sensitization and represent unique lymphocytes involved in primary host defense. NKR-P1 is thought to be one of NK receptors mediating activation signals because cross-linking of NKR-P1 activates NK cells to exhibit cytotoxicity and IFN-γ production. However, molecular mechanism of NK cell activation via NKR-P1 is not well elucidated. In this study, we analyzed the cell surface complex associated with NKR-P1 on NK cells and found that NKR-P1 associates with the FcRγ chain which is an essential component of Fc receptors for IgG and IgE. The association between FcRγ and NKR-P1 is independent of Fc receptor complexes. Furthermore, NK cells from FcRγ-deficient mice did not show cytotoxicity or IFN-γ production upon NKR-P1 cross-linking. Similarly, NK1.1+ T cells from FcRγ-deficient mice did not produce IFN-γ upon NKR-P1 crosslinking. These findings demonstrate that the FcRγ chain plays an important role in activation of NK cells via the NKR-P1 molecule.