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NK cells are major effector cells involved in the elimination of early tumors and prevent metastasis. They often have an impaired function in patients with cancer. Preclinical studies have demonstrated NK cell activation as the adjunctive effect of invariant NKT (iNKT) cells. Activation of iNKT cells after administration of the glycolipid ligand α-galactosylceramide, loaded with CD1d-expressing human PBMC-derived APCs (APC/Gal), is an attractive cancer therapy to optimize the use of NK cells. However, the subsets of NK cells that are activated following iNKT cell activation as well as the period of NK cell activation remain unclear. In this study, we report that the granzyme B–expressing NK cell response in postoperative lung cancer patients was enhanced 49 d after administration of APC/Gal in a phase II study. We found maximum IFN-γ production on day 49 in 13 out of 27 APC/Gal-treated patients. On day 49, 14 out of 27 patients (51.9%) had higher IFN-γ production by iNKT cells (>6-fold higher than the baseline level). This increment significantly correlated with granzyme B–expressing NK cells. Although IFN-γ production was lower in patients in the nontreated group, we detected maximum IFN-γ production 12 mo after the resection of lung cancer (9 out of 29 patients [31%]). These findings suggest that elimination of cancer cells leads to increased NK cell function, which can be further enhanced by APC/Gal therapy.

The efficacy of current coronavirus disease 2019 (COVID-19) vaccines has been demonstrated; however, emerging evidence suggests insufficient protection in certain immunocompromised cancer patients. We previously developed a cell-based anti-cancer vaccine platform involving artificial adjuvant vector cells (aAVCs) capable of inducing a strong adaptive response by enhancing the innate immunity. aAVCs are target antigen-transfected allogenic cells that simultaneously express the natural killer T-cell ligand-CD1d complex on their surface. In the present study, we applied this system for targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (CoV-2-S) using CoV-2-S-expressing aAVCs (aAVC-CoV-2) and evaluated the immune response in a murine model. A single dose of aAVC-CoV-2 induced a large amount of CoV-2-S-specific, multifunctional CTLs in addition to CD4

NY-ESO-1 is a cancer/testis antigen expressed in various cancer types. However, the induction of NY-ESO-1-specific CTLs through vaccines is somewhat difficult. Thus, we developed a new type of artificial adjuvant vector cell (aAVC-NY-ESO-1) expressing a CD1d-NKT cell ligand complex and a tumor-associated antigen, NY-ESO-1. First, we determined the activation of invariant natural killer T (iNKT) and natural killer (NK) cell responses by aAVC-NY-ESO-1. We then showed that the NY-ESO-1-specific CTL response was successfully elicited through aAVC-NY-ESO-1 therapy. After injection of aAVC-NY-ESO-1, we found that dendritic cells (DCs) in situ expressed high levels of costimulatory molecules and produced interleukn-12 (IL-12), indicating that DCs undergo maturation in vivo. Furthermore, the NY-ESO-1 antigen from aAVC-NY-ESO-1 was delivered to the DCs in vivo, and it was presented on MHC class I molecules. The cross-presentation of the NY-ESO-1 antigen was absent in conventional DC-deficient mice, suggesting a host DC-mediated CTL response. Thus, this strategy helps generate sufficient CD8

Eomes regulates the differentiation of CD8+ T cells into effector and memory phases. However, its role in invariant (i)NKT cells remains unknown. Here, we show the impact of Eomes on iNKT cells in the thymus and peripheral tissue using conditional knockout (Eomes-cKO) mice. In the thymus, CD1d-tetramer+CD24+CD44−NK1.1−CD69+stage 0 iNKT cells express higher levels of Eomes than the other iNKT stages. We also found that Eomes regulates NKT1 cell differentiation predominantly. Interestingly, the expression of Eomes in the steady state is low, but can be upregulated after TCR stimulation. We also showed epigenetic changes in the Eomes locus after activation. In addition, vaccination of C57BL/6, but not Eomes-cKO mice with iNKT ligand-loaded dendritic cells generated KLRG1+iNKT cells in lung, characterized as effector memory phenotype by transcriptome profiling. Thus, Eomes regulates not only the differentiation of NKT1 cells in the thymus, but also their differentiation into memory-like KLRG1+iNKT cells in the periphery., Kanako Shimizu, Yusuke Sato et al. examine the impact of the Eomes transcription factor on invariant NKT (iNKT) cell differentiation using conditional knockout mice. They show that Eomes is needed for the development of iNKT1 cells in the thymus, and for their activation and differentiation in peripheral tissues.

Granzyme A (GzmA), together with perforin, are well-known for their cytotoxic activity against tumor or virus-infected cells. In addition to this cytotoxic function, GzmA stimulates several immune cell types and induces inflammation in the absence of perforin, however, its effect on the dendritic cell (DC) is unknown. In the current study, we showed that recombinant GzmA induced the phenotypic maturation of plasmacytoid DCs (pDCs) and conventional DCs (cDCs), but not their apoptosis. Particularly, GzmA made pDCs more functional, thus leading to production of type I interferon (IFN) via the TLR9-MyD88 pathway. We also demonstrated that GzmA binds TLR9 and co-localizes with it in endosomes. When co-administered with antigen, GzmA acted as a powerful adjuvant for eliciting antigen-specific cytotoxic CD8+ T lymphocytes (CTLs) that protected mice from tumor challenge. The induction of CTL was completely abolished in XCR1+ DC-depleted mice, whereas it was reduced to less than half in pDC-depleted or IFN-α/β receptor knockout mice. Thus, CTL cross-priming was dependent on XCR1+cDC and also type I IFN, which was produced by GzmA-activated pDCs. These results indicate that GzmA -stimulated pDCs enhance the cross-priming activity of cDCs in situ. We also showed that the adjuvant effect of GzmA is superior to CpG-ODN and LPS. Our findings highlight the ability of GzmA to bridge innate and adaptive immune responses via pDC help and suggest that GzmA may be useful as a vaccine adjuvant.

Recent immunotherapies have shown clinical success. In particular, vaccines based on particulate antigen (Ag) are expected to be implemented based on their efficacy. In the current study, we describe a strategy entailing Ag-encapsulating PEG-modified liposomes (PGL-Ag) as antigen protein delivery devices and show that the success of the liposome depends on the antigen-presenting cell (APC) capacity; after administration of PGL-Ag, dendritic cells (DCs) in particular take up the Ag and subsequently prime T cells. For the generation of antitumor T cell responses in the lymphoid tissues, the function of encapsulated Ag-capturing DCs in vivo could be a biomarker. We next designed a prime-boost strategy to enhance the antitumor effects of the PGL-Ag. In the tumor sites, we show that Ag retention in nanoparticle-capturing DCs promotes a robust antitumor response. Thus, this efficient particulate Ag-based host antigen-presenting cell delivery strategy provides a bridge between innate and adaptive immune response and offers a novel therapeutic option against tumor cells.

The humoral immune response, also called the antibody-mediated immune response, is one of the main adaptive immune systems. The essential micronutrient zinc (Zn) is known to modulate adaptive immune responses, and dysregulated Zn homeostasis leads to immunodeficiency. However, the molecular mechanisms underlying this Zn-mediated modulation are largely unknown. Here, we show that the Zn transporter SLC39A10/ZIP10 plays an important role in B-cell antigen receptor (BCR) signal transduction. Zip10-deficiency in mature B cells attenuated both T-cell-dependent and -independent immune responses in vivo. The Zip10-deficient mature B cells proliferated poorly in response to BCR cross-linking, as a result of dysregulated BCR signaling. The perturbed signaling was found to be triggered by a reduction in CD45R phosphatase activity and consequent hyperactivation of LYN, an essential protein kinase in BCR signaling. Our data suggest that ZIP10 functions as a positive regulator of CD45R to modulate the BCR signal strength, thereby setting a threshold for BCR signaling in humoral immune responses.

The immune system is influenced by the vital zinc (Zn) status, and Zn deficiency triggers lymphopenia; however, the mechanisms underlying Zn-mediated lymphocyte maintenance remain elusive. Here we investigated ZIP10, a Zn transporter expressed in the early B-cell developmental process. Genetic ablation of Zip10 in early B-cell stages resulted in significant reductions in B-cell populations, and the inducible deletion of Zip10 in pro-B cells increased the caspase activity in parallel with a decrease in intracellular Zn levels. Similarly, the depletion of intracellular Zn by a chemical chelator resulted in spontaneous caspase activation leading to cell death. Collectively, these findings indicated that ZIP10-mediated Zn homeostasis is essential for early B-cell survival. Moreover, we found that ZIP10 expression was regulated by JAK-STAT pathways, and its expression was correlated with STAT activation in human B-cell lymphoma, indicating that the JAK-STAT-ZIP10-Zn signaling axis influences the B-cell homeostasis. Our results establish a role of ZIP10 in cell survival during early B-cell development, and underscore the importance of Zn homeostasis in immune system maintenance.

An induction of long-term cellular and humoral immunity is for the goal of vaccines, but the combination of antigens and adjuvant remain unclear. Here, we show, using a cellular vaccine carrying foreign protein antigen plus iNKT cell glycolipid antigen, designated as artificial adjuvant vector cells (aAVCs), that mature XCR1− DCs in situ elicit not only ordinal antigen-specific CD4+T cells, but also CD4+ Tfh and germinal center, resulted in inducing long-term antibody production. As a mechanism for leading the long-term antibody production by aAVC, memory CD4+ Tfh cells but not iNKTfh cells played an important role in a Bcl6 dependent manner. To develop it for influenza infection, we established influenza hemagglutinin-carrying aAVC (aAVC-HA) and found that all the mice vaccinated with aAVC-HA were protected from life-threatening influenza infection. Thus, the in vivo DC targeting therapy by aAVC would be useful for protection against viral infection.

Previous development studies of Thailand have focused on the authoritarian system and ideological aspects of “development, ” while ignoring the actual recipients of this ideology. This essay illustrates the media interpretation of the ideology of “development” during the Sarit Regime (1958-63), which was, incidentally, the first Thai government to implement a development promotion policy.Besides launching an economic policy through his National Economic Development Plan, Sarit tried to spread his ideas of development among the people through slogans and speeches, in order to inspire active people instilled with the “spirit of development” through such concepts as self-help, independence, and an understanding of the value of work, money, savings, and so on. Sarit provided an ideal “life roadmap” for the people and encouraged them to work for their happiness.A study of three Thai newspapers and one weekly magazine, however, reveals a gap existing between Sarit's images of development and those portrayed in the media. The media images may be characterized as follows. First, they portrayed development as a passive concept, regarding it as something given by the Government, and often used the phrases “receive development” and “demand development” from the Government, although Sarit had encouraged the people to embrace their own spirit of development. Secondly, the media perceived development as a government-organized “event, ” describing local development activities as venues with entertainment and dinner. Finally, the media did not understand the spirit of development in the way Sarit intended. Sarit tried to communicate his ideas about development to the people, but it seemingly in vain, for his audience thought he was simply issuing practical orders or regulations.The reasons for this gap between Sarit's images of development and those appearing in the media would seem to be as follows. First, Sarit's images did not correspond to his political style, which showed the kind of paternalism in which a ruler cares for his people like a father. Sarit's paternalism could well have been incompatible with the images of development, such as independence, that he tried to promote. Secondly, factors other than Sarit's efforts, such as new technologies or consumer goods entering Thailand during that period, influenced people's images of development which may have made it more difficult to communicate his intended meaning of the “spirit of development”.In conclusion, further discussion of development in Thailand would require additional further study and research into various aspects of development and images of development.