• Journal of Ginseng Research
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• v.31 no.3
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• pp.117-126
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• 2007

Ginseng, the root of Panax species, a well-known herbal medicine has been used as a traditional medicine for thousands of years and is now a popular and worldwide used natural medicine. Ginseng has been used primarily as a tonic to invigorate weak bodies to help the restoration of homeostasis in a wide range of pathological conditions such as cardiovascular diseases, cancer, immune deficiency and hepatotoxicity. Although conclusive clinical data in humans is still missing, recent research results have suggested that some of the active ingredients ginseng exert beneficial effects on central nervous system (CNS) disorders and neurodegenerative diseases, suggesting it could be used in treatment of psychotic disorders. Data from neural cell cultures and animal studies contribute to the understanding of these mechanisms that involve inhibitory effects on stress-induced corticosterone level increasing and modulating of neurontransmitters, reducing $Ca^{2+}$ over-influx, scavenging of free radicals and counteracting excitotoxicity. In this review, we focused on recently reported medicinal effects of ginseng and summarized the possibility of its applications on psychotic disorders.

• BMB Reports
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• v.55 no.7
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• pp.342-347
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• 2022

Defense priming allows plants to enhance their immune responses to subsequent pathogen challenges. Recent reports suggested that acquired resistances in parental generation can be inherited into descendants. Although epigenetic mechanisms are plausible tools enabling the transmission of information or phenotypic traits induced by environmental cues across generations, the mechanism for the transgenerational inheritance of defense priming in plants has yet to be elucidated. With the initial aim to elucidate an epigenetic mechanism for the defense priming in plants, we reassessed the transgenerational inheritance of plant defense, however, could not observe any evidence supporting it. By using the same dipping method with previous reports, Arabidopsis was exposed repeatedly to Pseudomonas syringae pv tomato DC3000 (Pst DC3000) during vegetative or reproductive stages. Irrespective of the developmental stages of parental plants that received pathogen infection, the descendants did not exhibit primed resistance phenotypes, defense marker gene (PR1) expression, or elevated histone acetylation within PR1 chromatin. In assays using the pressure-infiltration method for infection, we obtained the same results as above. Thus, our results suggest that the previous observations on the transgenerational inheritance of defense priming in plants should be more extensively and carefully reassessed.

• IMMUNE NETWORK
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• v.23 no.1
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• pp.5.1-5.28
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• 2023

Th cell lineage determination and functional specialization are tightly linked to the activation of lineage-determining transcription factors (TFs) that bind cis-regulatory elements. These lineage-determining TFs act in concert with multiple layers of transcriptional regulators to alter the epigenetic landscape, including DNA methylation, histone modification and threedimensional chromosome architecture, in order to facilitate the specific Th gene expression programs that allow for phenotypic diversification. Accumulating evidence indicates that Th cell differentiation is not as rigid as classically held; rather, extensive phenotypic plasticity is an inherent feature of T cell lineages. Recent studies have begun to uncover the epigenetic programs that mechanistically govern T cell subset specification and immunological memory. Advances in next generation sequencing technologies have allowed global transcriptomic and epigenomic interrogation of CD4+ Th cells that extends previous findings focusing on individual loci. In this review, we provide an overview of recent genome-wide insights into the transcriptional and epigenetic regulation of CD4+ T cell-mediated adaptive immunity and discuss the implications for disease as well as immunotherapies.

• BMB Reports
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• v.57 no.1
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• pp.40-49
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• 2024

Prokaryotes encode clustered regularly interspaced short palindromic repeat (CRISPR) arrays and CRISPR-associated (Cas) genes as an adaptive immune machinery. CRISPR-Cas systems effectively protect hosts from the invasion of foreign enemies, such as bacteriophages and plasmids. During a process called 'adaptation', non-self-nucleic acid fragments are acquired as spacers between repeats in the host CRISPR array, to establish immunological memory. The highly conserved Cas1-Cas2 complexes function as molecular recorders to integrate spacers in a time course manner, which can subsequently be expressed as crRNAs complexed with Cas effector proteins for the RNA-guided interference pathways. In some of the RNA-targeting type III systems, Cas1 proteins are fused with reverse transcriptase (RT), indicating that RT-Cas1-Cas2 complexes can acquire RNA transcripts for spacer acquisition. In this review, we summarize current studies that focus on the molecular structure and function of the RT-fused Cas1-Cas2 integrase, and its potential applications as a directional RNA-recording tool in cells. Furthermore, we highlight outstanding questions for RT-Cas1-Cas2 studies and future directions for RNA-recording CRISPR technologies.

• IMMUNE NETWORK
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• v.20 no.1
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• pp.2.1-2.19
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• 2020

Acute viral infection or vaccination generates highly functional memory CD8 T cells following the Ag resolution. In contrast, persistent antigenic stimulation in chronic viral infection and cancer leads to a state of T-cell dysfunction termed T-cell exhaustion. We and other have recently identified a novel subset of exhausted CD8 T cells that act as stem cells for maintaining virus-specific CD8 T cells in a mouse model of chronic lymphocytic choriomeningitis virus infection. This stem cell-like CD8 T-cell subset has been also observed in both mouse and human tumor models. Most importantly, in both chronic viral infection and tumor models, the proliferative burst of Ag-specific CD8 T cells driven by PD-1-directed immunotherapy comes exclusively from this stem cell-like CD8 T-cell subset. Therefore, a better understanding of the mechanisms how CD8 T-cell subsets are regulated during chronic viral infection and cancer is required to improve the current immunotherapies that restore the function of exhausted CD8 T cells. In this review, we discuss the differentiation of virus-specific CD8 T cells during chronic viral infection, the characteristics and function of CD8 T-cell subsets, and the therapeutic intervention of PD-1-directed immunotherapy in cancer.

• IMMUNE NETWORK
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• v.14 no.1
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• pp.21-29
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• 2014

Follicular helper T ($T_{FH}$) cells are recently highlighted as their crucial role for humoral immunity to infection as well as their abnormal control to induce autoimmune disease. During an infection, na$\ddot{i}$ve T cells are differentiating into $T_{FH}$ cells which mediate memory B cells and long-lived plasma cells in germinal center (GC). $T_{FH}$ cells are characterized by their expression of master regulator, Bcl-6, and chemokine receptor, CXCR5, which are essential for the migration of T cells into the B cell follicle. Within the follicle, crosstalk occurs between B cells and $T_{FH}$ cells, leading to class switch recombination and affinity maturation. Various signaling molecules, including cytokines, surface molecules, and transcription factors are involved in $T_{FH}$ cell differentiation. IL-6 and IL-21 cytokine-mediated STAT signaling pathways, including STAT1 and STAT3, are crucial for inducing Bcl-6 expression and $T_{FH}$ cell differentiation. $T_{FH}$ cells express important surface molecules such as ICOS, PD-1, IL-21, BTLA, SAP and CD40L for mediating the interaction between T and B cells. Recently, two types of microRNA (miRNA) were found to be involved in the regulation of $T_{FH}$ cells. The miR-17-92 cluster induces Bcl-6 and $T_{FH}$ cell differentiation, whereas miR-10a negatively regulates Bcl-6 expression in T cells. In addition, follicular regulatory T ($T_{FR}$) cells are studied as thymus-derived $CXCR5^+PD-1^+Foxp3^+\;T_{reg}$ cells that play a significant role in limiting the GC response. Regulation of $T_{FH}$ cell differentiation and the GC reaction via miRNA and $T_{FR}$ cells could be important regulatory mechanisms for maintaining immune tolerance and preventing autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Here, we review recent studies on the various factors that affect $T_{FH}$ cell differentiation, and the role of $T_{FH}$ cells in autoimmune diseases.

• IMMUNE NETWORK
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• v.20 no.5
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• pp.43.1-43.11
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• 2020

Capicua (CIC) is a transcriptional repressor that regulates several developmental processes. CIC deficiency results in lymphoproliferative autoimmunity accompanied by expansion of CD44^hiCD62L^lo effector/memory and follicular Th cell populations. Deletion of Cic alleles in hematopoietic stem cells (Vav1-Cre-mediated knockout of Cic) causes more severe autoimmunity than that caused by the knockout of Cic in CD4⁺CD8⁺ double positive thymocytes (Cd4-Cre-mediated knockout of Cic). In this study, we compared splenic CD4⁺ T cell activation and proliferation between whole immune cell-specific Cic-null (Cic^f/f;Vav1-Cre) and T cell-specific Cic-null (Cic^f/f;Cd4-Cre) mice. Hyperactivation and hyperproliferation of CD4⁺ T cells were more apparent in Cic^f/f;Vav1-Cre mice than in Cic^f/f;Cd4-Cre mice. Cic^f/f;Vav1-Cre CD4⁺ T cells more rapidly proliferated and secreted larger amounts of IL-2 upon TCR stimulation than did Cic^f/f;Cd4-Cre CD4⁺ T cells, while the TCR stimulation-induced activation of the TCR signaling cascade and calcium flux were comparable between them. Mixed wild-type and Cic^f/f;Vav1-Cre bone marrow chimeras also exhibited more apparent hyperactivation and hyperproliferation of Cic-deficient CD4⁺ T cells than did mixed wild-type and Cic^f/f;Cd4-Cre bone marrow chimeras. Taken together, our data demonstrate that CIC deficiency at the beginning of T cell development endows peripheral CD4⁺ T cells with enhanced T cell activation and proliferative capability.

• IMMUNE NETWORK
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• v.9 no.4
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• pp.127-132
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• 2009

Background: Toll-like receptors (TLRs) play a fundamental role in innate immunity through their capacity to recognize pathogen-associated molecular patterns. Also, TLRs that are expressed in T cells are reported to function as co-stimulatory receptors. However, the functional capacity of TLRs on CD4 T and CD8 T cells has not been directly compared. Here we compared CD4 and CD8 T cell responses to TLR2 ligand plus TCR-mediated stimulation. Methods: TLR2 expression was analyzed on T cell subsets under naive and alloantigen-primed conditions. We analyzed the effects of TLR2 co-stimulation on proliferation and survival of T cell subsets in vitro when stimulated with soluble anti-CD3 in the presence or absence of synthetic ligand $Pam_3CSK_4$. Results: TLR2 expression on CD8 T cells was induced following activation; this expression was much higher than on CD4 T cells. Thus, the molecule was constitutively expressed on Listeriaspecific memory CD8 T cells. Based on these expression levels, proliferation and survival were markedly elevated in CD8 T cells in response to the TLR2 co-stimulation by $Pam_3CSK_4$ compared with those in CD4 T cells. Conclusion: Our data show that TLR2 co-stimulation is more responsible for proliferation and survival of CD8 T cells than for that of CD4 T cells.

• IMMUNE NETWORK
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• v.11 no.5
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• pp.299-306
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• 2011

Background: $CD4^+Fop3^+$ regulatory T cells (Tregs) are needed to maintain peripheral tolerance, but their role in the development of autoimmune arthritis is still debated. The present study was undertaken to investigate the mechanism by which Tregs influence autoimmune arthritis, using a mouse model entitled K/BxN. Methods: We generated Treg-deficient K/BxNsf mice by congenically crossing K/BxN mice with Foxp3 mutant scurfy mice. The arthritic symptoms of the mice were clinically and histopathologically examined. The proportions and activation of $CD4^+$ T cells and/or dendritic cells were assessed in the spleens, draining lymph nodes and synovial tissue of these mice. Results: K/BxNsf mice exhibited earlier onset and more aggressive progression of arthritis than their K/BxN littermates. In particular, bone destruction associated with the influx of numerous RANKL+ cells into synovia was very prominent. They also contained more memory phenotype $CD4^+$ T cells, more Th1 and Th2 cells, and fewer Th17 cells than their control counterparts. Plasmacytoid dendritic cells expressing high levels of CD86 and CD40 were elevated in the K/BxNsf synovia. Conclusion: We conclude that Tregs oppose the progression of arthritis by inhibiting the development of $RANKL^+$ cells, homeostatically proliferating $CD4^+$ T cells, Th1, Th2 and mature plasmacytoid dendritic cells, and by inhibiting their influx into joints.

• IMMUNE NETWORK
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• v.4 no.3
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• pp.143-154
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• 2004

Background: CD27 is recently known as a memory B cell marker and is mainly expressed in activated T cells, some B cell population and NK cells. CD27 is a member of tumor necrosis factor receptor family. Like CD40 molecule, CD27 has (P/S/T/A) X(Q/E)E motif for interacting with TNF receptor-associated factors (TRAFs), and TRAF2 and TRAF5 bindings to CD27 in 293T cells were reported. Methods: To investigate the CD27 signaling effect in B cells, human CD40 extracellular domain containing mouse CD27 cytoplamic domain construct (hCD40-mCD27) was transfected into mouse B cell line CH12.LX and M12.4.1. Results: Through the stimulation of hCD40-mCD27 molecule via anti-human CD40 antibody or CD154 ligation, expression of CD11a, CD23, CD54, CD70 and CD80 were increased and secretion of IgM was induced, which were comparable to the effect of CD40 stimulation. TRAF2 and TRAF3 were recruited into lipid-enriched membrane raft and were bound to CD27 in M12.4.1 cells. CD27 stimulation, however, did not increase TRAF2 or TRAF3 degradation. Conclusion: In contrast to CD40 signaling pathway, TRAF2 and TRAF3 degradation was not observed after CD27 stimulation and it might contribute to prolonged B cell activation through CD27 signaling.