• IMMUNE NETWORK
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• v.11 no.6
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• pp.336-341
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• 2011

T cell receptor (TCR) signaling plays a critical role in T cell development, survival and differentiation. In the thymus, quantitative and/or qualitative differences in TCR signaling determine the fate of developing thymocytes and lead to positive and negative selection. Recently, it has been suggested that self-reactive T cells, escape from negative selection, should be suppressed in the periphery by regulatory T cells (Tregs) expressing Foxp3 transcription factor. Foxp3 is a master factor that is critical for not only development and survival but also suppressive activity of Treg. However, signals that determine Treg fate are not completely understood. The availability of mutant mice which harbor mutations in TCR signaling mediators will certainly allow to delineate signaling events that control intrathymic (natural) Treg (nTreg) development. Thus, we summarize the recent progress on the role of TCR signaling cascade components in nTreg development from the studies with murine model.

• Korean Journal of Veterinary Research
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• v.52 no.3
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• pp.183-191
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• 2012

The maintenance of peripheral immune tolerance and prevention of chronic inflammation and autoimmune disease require $CD4^{+}CD25^{+}$ T cells (regulatory T cells). The transcription factor Foxp3 is essential for the development of functional, regulatory T cells, which plays a prominent role in self-tolerance. Retroviral vectors can confer high level of gene transfer and transgene expression in a variety of cell types. Here we observed that following retroviral vector-mediated gene transfer of Foxp3, transductional Foxp3 expression was increased in the liver, lung, brain, heart, muscle, spinal cord, kidney and spleen. One day after vector administration, high levels of transgene and gene expression were observed in liver and lung. At 2 days after injection, transductional Foxp3 expression level was increased in brain, heart, muscle and spinal cord, but kidney and spleen exhibited a consistent low level. This finding was inconsistent with the increase in both $CD4^{+}CD25^{+}$ T cell and $CD4^{+}Foxp3^{+}$ T cell frequencies observed in peripheral immune cells by fluorescence-activated cell-sorting (FACS) analysis. Retroviral vector-mediated gene transfer of Foxp3 did not lead to increased numbers of $CD4^{+}CD25^{+}$ T cell and $CD4^{+}Foxp3^{+}$ T cell. These results demonstrate the level and duration of transductional Foxp3 gene expression in various tissues. A better understanding of Foxp3 regulation can be useful in dissecting the cause of regulatory T cells dysfunction in several autoimmune diseases and raise the possibility of enhancing suppressive functions of regulatory T cells for therapeutic purposes.

• Parasites, Hosts and Diseases
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• v.50 no.1
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• pp.29-35
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• 2012

The aim of the study is to characterize the phenotypes of $CD4^+$ $CD25^+$ T regulatory cells within the liver granulomas and association with both Foxp-3 gene expression and splenic cytokines. Naive C57BL/6 mice were intravenously injected with multiple doses of the soluble egg antigen (SEA) 7 days before cercarial infection. The immunized and infected control groups were sacrificed 8 and 16 weeks post-infection (PI). Histopathology, parasitological parameters, splenic phenotypes for T regulatory cells, the FOXP-3 expression in hepatic granuloma using real-time PCR, and the associated splenic cytokines were studied. Histopathological examination of the liver revealed remarkable increase in degenerated ova within hepatic granuloma which decreased in diameter at weeks 8 and 16 PI ($P$<0.01). The percentage of T regulatory cells ($CD4^+$ $CD25^+$) increased significantly ($P$<0.01) in the immunized group compared to the infected control at weeks 8 and 16 PI. The FOXP-3 expression in hepatic granulomas increased from 10 at week 8 to 30 fold at week 16 PI in the infected control group. However, its expression in the immunized group showed an increase from 30 at week 8 to 70 fold at week 16 PI. The splenic cytokine levels of pro-inflammatory cytokines, IFN-${\gamma}$, IL-4, and TNF-${\alpha}$, showed significant decreases ($P$<0.05) compared to the infected control group. In conclusion, the magnitude and phenotype of the egg-induced effects on T helper responses were found to be controlled by a parallel response within the T regulatory population which provides protection in worm parasite-induced immunopathology.

• Molecules and Cells
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• v.25 no.1
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• pp.64-69
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• 2008

Although the arthritis symptoms observed in the K/BxN model have been shown to be dependent on the functions of T and B cells specific to the self antigen glucose-6-phosphate isomerase, less is known about the in vivo roles of $CD4^{+}CD25^{+}$ regulatory T($T_{reg}$) cells in the pathology of K/BxN mice. We determined the quantitative and functional characteristics of the $T_{reg}$ cells in K/BxN mice. These mice contained a higher percentage of $Foxp3^+\;T_{reg}$ cells among the $CD4^+$ T cells than their BxN littermates. These $T_{reg}$ cells were anergic and efficiently suppressed the proliferation of $na\ddot{i}ve$ $CD4^+$ T cells and cytokine production by effector $CD4^+$ T cells in vitro. Antibody-mediated depletion of $CD25^+$ cells caused K/BxN mice to develop multi-organ inflammation and autoantibody production, while the symptoms of arthritis were not affected. These results demonstrate that despite the inability of the $T_{reg}$ cells to suppress arthritis development, they play a critical role protecting the arthritic mice from systemic expansion of autoimmunity.

• The Korea Journal of Herbology
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• v.24 no.1
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• pp.73-78
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• 2009

Objectives : In this study, we studied the effect of Pinellia Ternata (PT) on regulatory T cells and CD3+CCR3+ Th2 cells number in asthma model mice. Methods : All mice were immunized on two different days (21 days and 7 days before inhalational exposure) by i.p. injections of 0.2 $m\ell$ alum-precipitated Ag containing 100 ${\mu}g$ of OVA bound to 4 mg of aluminum hydroxide in PBS. Seven days after the second sensitization, mice were exposed to aerosolized ovalbumin for 30 min/day on 3 days/week for 12 weeks(at a flow rate of 250 L/min, 2.5％ ovalbumin in normal saline) and PT (400, 200 mg/kg) were orally administered 3 times a week for 8 weeks. After C57BL/6 mice were orally given of PT, the percentages, cell numbers, phenotype and function of CD4+CD25+Treg cells were determined by flow cytometry. Results : The cell numbers of CD4+CD25+Treg cell subsets were markedly increased in PT treated mice as reported. However, PT significantly reduced the CD3+CCR3+ Th2 cells in PBMC and lung of mice. Conclusions : These results indicate that PT has a deep inhibitory effect on asthma model mice by increase the number of regulatory T cells, and by reducing CD3+CCR3+ Th2 cells.

• IMMUNE NETWORK
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• v.12 no.5
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• pp.217-221
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• 2012

Fibroblast-like synoviocytes (FLS) colocalize with leukocyte infiltrates in rheumatoid synovia. Proinflammatory leukocytes are known to amplify inflammation by signaling to FLS, but crosstalk between FLS and regulatory T cells (Tregs) remains uncharacterized. To address this possibility, we cocultured FLS lines derived from arthritic mice with Tregs. FLS that expressed the ligand for glucocorticoid-induced TNF receptor family-related gene (GITR) decreased expression of Foxp3 and GITR in Tregs in a contact-dependent manner. This effect was abolished by blocking antibody to GITR. On the other hand, the Tregs caused the FLS to increase IL-6 production. These results demonstrate that inflamed FLS license Tregs to downregulate Foxp3 expression via the GITRL/GITR interaction while the Tregs induce the FLS to increase their production of IL-6. Our findings suggest that the interaction between FLS and Tregs dampens the anti-inflammatory activity of Tregs and amplifies the proinflammatory activity of FLS, thereby exacerbating inflammatory arthritis.

• Journal of Microbiology and Biotechnology
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• v.17 no.2
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• pp.348-358
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• 2007

Metallothionein, a cysteine-rich stress response protein that is naturally induced by a variety of immunologic stressors, has been shown to suppress autoimmune disorders through mechanisms not yet fully defined. In the present study, we examined the underlying mechanisms by which metallothionein might mediate such regulation of autoimmunity. $Na\ddot{i}ve\;CD4^+$ T cells from metallothionein-deficient mice differentiated to produce significantly less IL-10, $TGF-{\gamma}$, and repressor of GATA, but more $IFN-{\gamma}$ and T-bet, when compared with those from wild-type mice. The levels of IL-4 and GATA-3 production were not different between the two groups of mice. Conversely, treatment with exogenous metallothionein during the priming phase drove $na\ddot{i}ve$ wild-type $CD4^+\;T$ cells to differentiate into cells producing more IL-10 and $TGF-{\beta}$, but less $IFN-{\gamma}$ than untreated cells. Metallothionein-primed cells were hyporesponsive to restimulation, and suppressive to T cell proliferation in an IL-10-dependent manner. Lymphocytes from metallothionein-deficient mice displayed significantly elevated levels of AP-1 and JNK activities in response to stimulation compared with those from wild-type controls. Importantly, transgenic mice overexpressing metallothionein exhibited significantly reduced susceptibility to collagen-induced arthritis and enhanced IL-10 level in the serum, relative to their nontransgenic littermates. Taken together, these data suggest that metallothionein is able to promote the generation of IL-10-and $TGF-{\beta}$-producing type 1 regulatory T-like cells by downregulating JNK-dependent AP-1 activity. Thus, metallothionein may play an important role in the regulation of Th1-dependent autoimmune arthritis, and may represent both a potential target for therapeutic manipulation and a critical element in the diagnostic assessment of disease potential.

• Hanyang Medical Reviews
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• v.33 no.1
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• pp.10-16
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• 2013

Follicular helper T cells (Tfh) play a significant role in providing T cell help to B cells during the germinal center reaction, where somatic hypermutation, affinity maturation, isotype class switching, and the differentiation of memory B cells and long-lived plasma cells occur. Antigen-specific T cells with IL-6 and IL-21 upregulate CXCR5, which is required for the migration of T cells into B cell follicles, where these T cells mature into Tfh. The surface markers including PD-1, ICOS, and CD40L play a significant role in providing T cell help to B cells. The upregulation of transcription factor Bcl-6 induces the expression of CXCR5, which is an important factor for Tfh differentiation, by inhibiting the expression of other lineage-specific transcription factors such as T-bet, GATA3, and RORγt. Surprisingly, recent evidence suggests that CD4 T cells already committed to Th1, Th2, and Th17 cells obtain flexibility in their differentiation programs by downregulating T-bet, GATA3, and RORγt, upregulating Bcl-6 and thus convert into Tfh. Limiting the numbers of Tfh within germinal centers is important in the regulation of the autoantibody production that is central to autoimmune diseases. Recently, it was revealed that the germinal center reaction and the size of the Tfh population are also regulated by thymus-derived follicular regulatory T cells (Tfr) expressing CXCR5 and Foxp3. Dysregulation of Tfh appears to be a pathogenic cause of autoimmune disease suggesting that tight regulation of Tfh and germinal center reaction by Tfr is essential for maintaining immune tolerance. Therefore, the balance between Tfh and Tfr appears to be a critical peripheral tolerance mechanism that can inhibit autoimmune disorders.

• 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.3 no.3
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• pp.169-175
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• 2003

The intestinal immune system can discriminate between harmful and unharmful antigens and do not provoke productive immunity to unharmful antigen. Thus oral administration of antigen is one of classical methods for inducing antigen-specific immune tolerance in the periphery. Furthermore, oral tolerance has been investigated for the treatment of autoimmune disorders in human clinical trials. However, the detail mechanism of oral tolerance and contributing factors are not defined clearly at this time. Recent studies demonstrate unique types of immune cell that suppressing immune response, such as regulatory T cell and tolerogenic dendritic cell. This article reviews the factors involved in oral tolerance and discusses our current understanding base on the recent literatures and our works.