Immunological memory has been regarded as a unique feature of the adaptive immune response mediated in an antigen-specific manner by T and B lymphocytes. However, natural killer (NK) cells and γδT ...cells, which traditionally are classified as innate immune cells, have been shown in recent studies to have hallmark features of memory cells. Invariant NKT cell (iNKT cell)–mediated antitumor effects indicate that iNKT cells are activated in vivo by vaccination with iNKT cell ligand-loaded CD1d ⁺ cells, but not by vaccination with unbound NKT cell ligand. In such models, it previously was thought that the numbers of IFN-γ–producing cells in the spleen returned to the basal level around 1 wk after the vaccination. In the current study, we demonstrate the surprising presence of effector memory-like iNKT cells in the lung. We found long-term antitumor activity in the lungs of mice was enhanced after vaccination with iNKT cell ligand-loaded dendritic cells. Further analyses showed that the KLRG1 ⁺ (Killer cell lectin-like receptor subfamily G, member 1–positive) iNKT cells coexpressing CD49d and granzyme A persisted for several months and displayed a potent secondary response to cognate antigen. Finally, analyses of CDR3β by RNA deep sequencing demonstrated that some particular KLRG1 ⁺ iNKT-cell clones accumulated, suggesting the selection of certain T-cell receptor repertoires by an antigen. The current findings identifying effector memory-like KLRG1 ⁺ iNKT cells in the lung could result in a paradigm shift regarding the basis of newly developed extrathymic iNKT cells and could contribute to the future development of antitumor immunotherapy by uniquely energizing iNKT cells.
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population with the ability to suppress immune responses and are currently classified into three distinct MDSC subsets: monocytic, ...granulocytic and non-monocytic, and non-granulocytic MDSCs. Although NK cells provide an important first-line defense against newly transformed cancer cells, it is unknown whether NK cells can regulate MDSC populations in the context of cancer. In this study, we initially found that the frequency of MDSCs in non-Hodgkin lymphoma (NHL) patients was increased and inversely correlated with that of NK cells, but not that of T cells. To investigate the regulation of MDSC subsets by NK cells, we used an EL4 murine lymphoma model and found the non-monocytic and non-granulocytic MDSC subset, i.e., Gr1
+
CD11b
+
Ly6G
med
Ly6C
med
MDSC, is increased after NK cell depletion. The MDSC population that expresses MHC class II, CD80, CD124, and CCR2 is regulated mainly by CD27
+
CD11b
+
NK cells. In addition, this MDSC subset produces some immunosuppressive cytokines, including IL-10 but not nitric oxide (NO) or arginase. We also examined two subsets of MDSCs (CD14
+
HLA-DR
−
and CD14
−
HLA-DR
−
MDSC) in NHL patients and found that higher IL-10-producing CD14
+
HLA-DR
−
MDSC subset can be seen in lymphoma patients with reduced NK cell frequency in peripheral blood. Our analyses of MDSCs in this study may enable a better understanding of how MDSCs manipulate the tumor microenvironment and are regulated by NK cells in patients with lymphoma.
Occurrence of a CSF‐1 receptor‐dependent monocyte differentiation process driven by IL‐34, but not CSF‐1.
With the use of a mouse FDC line, FL‐Y, we have been analyzing roles for FDCs in controlling ...B cell fate in GCs. Beside these regulatory functions, we fortuitously found that FL‐Y cells induced a new type of CD11b+ monocytic cells (F4/80+, Gr‐1−, Ly6C−, I‐A/E−/lo, CD11c−, CD115+, CXCR4+, CCR2+, CX3CR1−) when cultured with a Lin−c‐kit+ population from mouse spleen cells. The developed CD11b+ cells shared a similar gene‐expression profile to mononuclear phagocytes and were designated as FDMCs. Here, we describe characteristic immunological functions and the induction mechanism of FDMCs. Proliferation of anti‐CD40 antibody‐stimulated B cells was markedly accelerated in the presence of FDMCs. In addition, the FDMC‐activated B cells efficiently acquired GC B cell‐associated markers (Fas and GL‐7). We observed an increase of FDMC‐like cells in mice after immunization. On the other hand, FL‐Y cells were found to produce CSF‐1 as well as IL‐34, both of which are known to induce development of macrophages and monocytes by binding to the common receptor, CSF‐1R, expressed on the progenitors. However, we show that FL‐Y‐derived IL‐34, but not CSF‐1, was selectively responsible for FDMC generation using neutralizing antibodies and RNAi. We also confirmed that FDMC generation was strictly dependent on CSF‐1R. To our knowledge, a CSF‐1R‐mediated differentiation process that is intrinsically specific for IL‐34 has not been reported. Our results provide new insights into understanding the diversity of IL‐34 and CSF‐1 signaling pathways through CSF‐1R.
Immunotherapy using dendritic cells (DCs) has the potential to activate both T cells and NK cells. We previously demonstrated the long-lasting antitumor responses by NK cells following immunization ...with bone marrow-derived DCs. In the current study, we demonstrate that long-term antitumor NK responses require endogenous DCs and a subset of effector memory CD4(+) T (CD4(+) T(EM)) cells. One month after DC immunization, injection of a tumor into DC-immunized mice leads to an increase in the expression of CXCL10 by endogenous DCs, thus directing NK cells into the white pulp where the endogenous DCs bridged CD4(+) T(EM) cells and NK cells. In this interaction, CD4(+) T(EM) cells express CD40L, which matures the endogenous DCs, and produce cytokines, such as IL-2, which activates NK cells. These findings suggest that DC vaccination can sustain long-term innate NK cell immunity but requires the participation of the adaptive immune system.
A key goal of vaccine immunotherapy is the generation of long-term memory CD8(+) T cells capable of mediating immune surveillance. We discovered a novel intercellular pathway governing the ...development of potent memory CD8(+) T cell responses against cell-associated Ags that is mediated through cross-presentation by XCR1(+) dendritic cells (DCs). Generation of CD8(+) memory T cells against tumor cells pulsed with an invariant NKT cell ligand depended on cross-talk between XCR1(+) and plasmacytoid DCs that was regulated by IFN-α/IFN-αR signals. IFN-α production by plasmacytoid DCs was stimulated by an OX40 signal from the invariant NKT cells, as well as an HMGB1 signal from the dying tumor cells. These findings reveal a previously unknown pathway of intercellular collaboration for the generation of tumor-specific CD8(+) memory T cells that can be exploited for strategic vaccination in the setting of tumor immunotherapy.
Both innate and adaptive immunity are crucial for cancer immunosurveillance, but precise therapeutic equations to restore immunosurveillance in patients with cancer patients have yet to be developed. ...In murine models, α-galactosylceramide (α-GalCer)-loaded, tumor antigen-expressing syngeneic or allogeneic cells can act as cellular adjuvants, linking the innate and adaptive immune systems. In the current study, we established human artificial adjuvant vector cells (aAVC) consisting of human HEK293 embryonic kidney cells stably transfected with the natural killer T (NKT) immune cell receptor CD1d, loaded with the CD1d ligand α-GalCer and then transfected with antigen-encoding mRNA. When administered to mice or dogs, these aAVC-activated invariant NKT (iNKT) cells elicited antigen-specific T-cell responses with no adverse events. In parallel experiments, using NOD/SCID/IL-2rγc(null)-immunodeficient (hDC-NOG) mouse model, we also showed that the human melanoma antigen, MART-1, expressed by mRNA transfected aAVCs can be cross-presented to antigen-specific T cells by human dendritic cells. Antigen-specific T-cell responses elicited and expanded by aAVCs were verified as functional in tumor immunity. Our results support the clinical development of aAVCs to harness innate and adaptive immunity for effective cancer immunotherapy.
Because of their unique role in linking the innate and adaptive immune systems, dendritic cells (DCs) have been a logical focus for novel immunotherapies. However, strategies employing active ...immunization with ex vivo generated and antigen-pulsed DCs have shown limited efficacy in clinical trials. These past approaches did not take into account the complex interactions between cells of the innate immune system and DCs during DC maturation, antigen processing, and presentation to naïve T cells. By better understanding the natural sequence of events occurring in vivo during an effective immune response, we can tailor antitumor immunotherapeutic strategies to augment aspects of this response from the activation of innate immune cells to antigen uptake and DC maturation to priming of naïve T cells and, ultimately, to the establishment of antitumor immunity. Current DC vaccination strategies utilize a number of methods to recapitulate the cascade of events that culminate in a protective antitumor immune response.
A nasal formulation of mometasone furoate (MF) is advantageous in avoiding systemic activity characteristic of glucocorticoids when it is applied topically. To confirm antiallergic effects of this ...glucocorticoid formulation elaborately, we investigated whether the drug can suppress the production of IgE antibodies and related cytokines. It we showed that IgE production induced in mice immunized via intranasal route was significantly reduced when the mice were administered MF intranasally. Further, MF was effective in inhibiting production of type-2 helper T cell cytokines in vivo and in vitro. These results provide a immunopharmacological basis for clinical efficacy of this drug.
A facile solvothermal synthesis in an ethanol/acetic acid mixture for the fabrication of SnO2 with a controllable hierarchical spherical size and micro-/mesoporosity is presented. SEM, TEM and N2 ...adsorption/desorption investigation unveiled that the obtained SnO2 spheres exhibited a particle size in the range of 0.6–1.6 μm and a pore size of about 1.4–1.9 nm depending on the volume ratio of acetic acid to ethanol in the reaction mixture, and the spheres were constructed by nanoscale particles. Due to its micro-/mesoporous structure, the SnO2 spheres exhibited large specific surface areas over 100 m2/g. When 10 vol. % of acetic acid at 200 °C for 20 h was used for the reaction, the obtained SnO2 possessed a higher specific surface area of 145 m2/g (SnO2_10). The gas sensing property of SnO2_10 without an additional noble metal co-catalyst exhibited a large toluene sensing response (Ra/Rg) of 20.2 at 400 °C, which was about 6 times higher and acceptable selectivity compared to those of other samples. The study found that the sensing performance in the SnO2 hierarchical spheres was influenced by several factors e.g. particle morphology, pore size and specific surface area rather than only a single parameter. Therefore, a precise control of those influencing parameters may lead to the optimum sensing property. These findings are important for the further development of the micro-/mesoporous metal-based oxide as an alternative successor for toluene gas sensor material.
Micro-/mesoporous SnO2 with a controllable particle size and pore-diameter synthesized by our novel process has exhibited a high responsivity to toluene gas. Display omitted
•A hierarchical nanostructure of SnO2 spheres with micro-/mesoporosity were successfully synthesized by a novel organic solution process.•The pore diameter, particle size and specific surface area of SnO2 can be controlled by adjusting the vol. % of acetic acid to ethanol.•The synthesized SnO2 showed a large surface area of 145 m2/g with pore size distribution of 1.4 nm.•The highest toluene sensing response (Ra/Rg) of the micro-/mesoporous SnO2 was 20.2 in 50 ppm of toluene.•The gas sensing response are influenced by particle size, pore diameter as well as specific surface area.
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