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1.
iScience ; 27(6): 109840, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38779479

RESUMO

Quantification of cytokine secretion has facilitated advances in the field of immunology, yet the dynamic and varied secretion profiles of individual cells, particularly those obtained from limited human samples, remain obscure. Herein, we introduce a technology for quantitative live-cell imaging of secretion activity (qLCI-S) that enables high-throughput and dual-color monitoring of secretion activity at the single-cell level over several days, followed by transcriptome analysis of individual cells based on their phenotype. The efficacy of qLCI-S was demonstrated by visualizing the characteristic temporal pattern of cytokine secretion of group 2 innate lymphoid cells, which constitute less than 0.01% of human peripheral blood mononuclear cells, and by revealing minor subpopulations with enhanced cytokine production. The underlying mechanism of this feature was linked to the gene expression of stimuli receptors. This technology paves the way for exploring gene expression signatures linked to the spatiotemporal dynamic nature of various secretory functions.

2.
Commun Biol ; 6(1): 915, 2023 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-37673922

RESUMO

The decision of whether cells are activated or not is controlled through dynamic intracellular molecular networks. However, the low population of cells during the transition state of activation renders the analysis of the transcriptome of this state technically challenging. To address this issue, we have developed the Time-Dependent Cell-State Selection (TDCSS) technique, which employs live-cell imaging of secretion activity to detect an index of the transition state, followed by the simultaneous recovery of indexed cells for subsequent transcriptome analysis. In this study, we used the TDCSS technique to investigate the transition state of group 2 innate lymphoid cells (ILC2s) activation, which is indexed by the onset of interleukin (IL)-13 secretion. The TDCSS approach allowed us to identify time-dependent genes, including transiently induced genes (TIGs). Our findings of IL4 and MIR155HG as TIGs have shown a regulatory function in ILC2s activation.


Assuntos
Imunidade Inata , Linfócitos , Imunidade Inata/genética , Perfilação da Expressão Gênica , Transcriptoma
3.
Adv Exp Med Biol ; 1365: 75-95, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35567742

RESUMO

The recent discovery of new innate lymphoid cells (ILCs) has revolutionized the field of allergies. Since most allergic diseases induce a type 2 immune response, Th2 cells, which produce IL-4, IL-5, and IL-13 in an antigen-dependent manner, in addition to basophils and mast cells which are activated by antigen-specific IgE, are thought to play a major role in the pathogenesis. However, since group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines (i.e., IL-2, IL-4, IL-5, IL-6, IL-9, IL-13, GM-CSF, and amphiregulin) in response to various cytokines, including IL-33 in the surrounding environment, the possibility has emerged that there are two types of allergies: allergies induced in an antigen-dependent manner by Th2 cells and allergies induced in an antigen-independent manner by ILC2s. In order to make an impact on the increasing incidence of allergic diseases in the world, it is essential to research and develop new treatments that focus not only on Th2 cells but also on ILC2s. In this chapter, the role of ILCs in allergic diseases, which has rapidly changed with the discovery of ILCs, is discussed, focusing mainly on ILC2s.


Assuntos
Hipersensibilidade , Interleucina-13 , Citocinas , Humanos , Imunidade Inata , Interleucina-4 , Interleucina-5 , Linfócitos
4.
Int Immunol ; 33(5): 251-259, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33403383

RESUMO

Group 2 innate lymphoid cells (ILC2s) are novel lymphocytes discovered in 2010. Unlike T or B cells, ILC2s are activated non-specifically by environmental factors and produce various cytokines, thus playing a role in tissue homeostasis, diseases including allergic diseases, and parasite elimination. ILC2s were first reported as cells abundantly present in fat-associated lymphoid clusters in adipose tissue. However, subsequent studies revealed their presence in various tissues throughout the body, acting as key players in tissue-specific diseases. Recent histologic analyses revealed that ILC2s are concentrated in specific regions in tissues, such as the lamina propria and perivascular regions, with their function being controlled by the surrounding cells, such as epithelial cells and other immune cells, via cytokine and lipid production or by cell-cell interactions through surface molecules. Especially, some stromal cells have been identified as the niche cells for ILC2s, both in the steady state and under inflammatory conditions, through the production of IL-33 or extracellular matrix factors. Additionally, peripheral neurons reportedly co-localize with ILC2s and alter their function directly through neurotransmitters. These findings suggest that the different localizations or different cell-cell interactions might affect the function of ILC2s. Furthermore, generally, ILC2s are thought to be tissue-resident cells; however, they occasionally migrate to other tissues and perform a new role; this supports the importance of the microenvironment for their function. We summarize here the current understanding of how the microenvironment controls ILC2 localization and function with the aim of promoting the development of novel diagnostic and therapeutic methods.


Assuntos
Comunicação Celular/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Animais , Microambiente Celular , Citocinas/imunologia , Células Epiteliais/imunologia , Humanos , Inflamação/imunologia
5.
Cell Rep ; 30(8): 2743-2757.e5, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32101749

RESUMO

Group 2 innate lymphoid cells (ILC2s) are abundant in non-lymphoid tissues and increase following infectious and inflammatory insults. In solid tumors, however, ILC2s constitute a relatively small proportion of immune cells. Here, we show, using melanoma as a model, that while the IL-33/IL C2/eosinophil axis suppresses tumor growth, tumor-derived lactate attenuates the function and survival of ILC2s. Melanomas with reduced lactate production (LDHAlow) are growth delayed and typified by an increased number of ILC2s compared with control tumors. Upon IL-33 stimulation, ILC2s accompanied by eosinophils more effectively restrain the growth of LDHAlow tumors than control melanomas. Furthermore, database analysis reveals a negative correlation between the expression of LDHA and markers associated with ILC2s and the association of high expression of IL33 and an eosinophil marker SIGLEC8 with better overall survival in human cutaneous melanoma patients. This work demonstrates that the balance between the IL-33/ILC2/eosinophil axis and lactate production by tumor cells regulates melanoma growth.


Assuntos
Imunidade Inata , Ácido Láctico/metabolismo , Linfócitos/imunologia , Melanoma Experimental/imunologia , Neoplasias Cutâneas/imunologia , Animais , Proliferação de Células , Sobrevivência Celular , Eosinófilos/imunologia , Feminino , Humanos , Interleucina-33/metabolismo , Interleucina-5/biossíntese , L-Lactato Desidrogenase/metabolismo , Masculino , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL
6.
Sci Rep ; 7(1): 7780, 2017 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-28798470

RESUMO

Hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma worldwide. However, the strategy of HBV to escape from the host immune system remains largely unknown. In this study, we examined extracellular vesicles (EVs) secreted from human hepatocytes infected with HBV. EVs includeing exosomes are nano-size vesicles with proteins, mRNAs, and microRNAs (miRNAs), which can be transmitted to different cells. We found that 104 EV associated miRNAs were increased in hepatocytes more than 2-fold by HBV infection. We then selected those that were potentially implicated in immune regulation. Among them, five HBV-induced miRNAs were found to potentially target multiple sequences in the 3'UTR of IL-21, a cytokine that induces anti-viral immunity. Moreover, expression of a reporter gene with the 3' UTR of human IL-21 mRNA was suppressed by the five miRNAs individually. Finally, IL-21 expression in cloned human T cells was down-regulated by the five miRNAs. Collectively, this study identified the novel 3' UTR sequences of human IL-21 mRNA and potential binding sites of HBV-induced EV-miRNAs.


Assuntos
Regiões 3' não Traduzidas , Interleucinas/genética , MicroRNAs/metabolismo , RNA Mensageiro/genética , Células Cultivadas , Vesículas Extracelulares/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Interleucinas/metabolismo , MicroRNAs/genética , RNA Mensageiro/química , RNA Mensageiro/metabolismo
7.
Proc Natl Acad Sci U S A ; 113(36): 10139-44, 2016 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-27551096

RESUMO

Natural killer (NK) cells are known to be activated by Th1-type cytokines, such as IL-2, -12, or -18, and they secrete a large amount of IFN-γ that accelerates Th1-type responses. However, the roles of NK cells in Th2-type responses have remained unclear. Because IL-4 acts as an initiator of Th2-type responses, we examined the characteristics of NK cells in mice overexpressing IL-4. In this study, we report that IL-4 overexpression induces distinctive characteristics of NK cells (B220(high)/CD11b(low)/IL-18Rα(low)), which are different from mature conventional NK (cNK) cells (B220(low)/CD11b(high)/IL-18Rα(high)). IL-4 overexpression induces proliferation of tissue-resident macrophages, which contributes to NK cell proliferation via production of IL-15. These IL-4-induced NK cells (IL4-NK cells) produce higher levels of IFN-γ, IL-10, and GM-CSF, and exhibit high cytotoxicity compared with cNK cells. Furthermore, incubation of cNK cells with IL-15 and IL-4 alters their phenotype to that similar to IL4-NK cells. Finally, parasitic infection, which typically causes strong Th2-type responses, induces the development of NK cells with characteristics similar to IL4-NK cells. These IL4-NK-like cells do not develop in IL-4Rα KO mice by parasitic infection. Collectively, these results suggest a novel role of IL-4 in immune responses through the induction of the unique NK cells.


Assuntos
Citotoxicidade Imunológica , Interleucina-15/imunologia , Interleucina-4/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária , Infecções por Strongylida/imunologia , Animais , Antígeno CD11b/genética , Antígeno CD11b/imunologia , Proliferação de Células , Regulação da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-15/genética , Interleucina-15/farmacologia , Interleucina-4/genética , Interleucina-4/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/parasitologia , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/imunologia , Macrófagos/imunologia , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nippostrongylus/imunologia , Nippostrongylus/patogenicidade , Receptores de Interleucina-18/genética , Receptores de Interleucina-18/imunologia , Receptores de Interleucina-4/deficiência , Receptores de Interleucina-4/genética , Receptores de Interleucina-4/imunologia , Transdução de Sinais , Infecções por Strongylida/genética , Infecções por Strongylida/parasitologia
8.
Eur J Immunol ; 44(9): 2638-47, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24995967

RESUMO

Mature NK cells are heterogeneous as to their expression levels of cell surface molecules. However, the functional differences and physiological roles of each NK-cell subset are not fully understood. In this study, we report that based on the Ly6C expression levels, mature C57BL/6 murine NK cells can be subdivided into Ly6C(low) and Ly6C(high) subsets. Ly6C(high) NK cells are in an inert state as evidenced by the production of lower levels of IFN-γ and granzyme B, and they exhibit poorer proliferative potential than Ly6C(low) NK cells. In addition, adoptive transfer experiments revealed that Ly6C(high) NK cells are derived from Ly6C(low) NK cells in the steady state. These results strongly suggest that Ly6C(high) NK cells are resting cells in the steady state. However, in vitro, Ly6C(high) NK cells become Ly6C(low) NK cells with strong effector functions upon stimulation with IL-15. Moreover, Ly6C(high) NK cells also revert to Ly6C(low) NK cells in vivo upon injection of the IL-15 inducers polyI:C and CpG. Taken together, these results demonstrate the plasticity of mature NK cells and suggest that Ly6C(high) NK cells are a reservoir of potential NK cells that allow effective and strong response to infections.


Assuntos
Antígenos Ly/imunologia , Proliferação de Células , Interferon gama/imunologia , Interleucina-15/imunologia , Animais , Granzimas/imunologia , Indutores de Interferon/farmacologia , Interleucina-15/farmacologia , Células Matadoras Naturais , Camundongos , Poli I-C/farmacologia
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