Adoptive transfer of all-trans-retinal-induced regulatory T cells ameliorates experimental autoimmune arthritis in an interferon-gamma knockout model

Jeon, Eun-Joo,Yoon, Bo-Young,Lim, Jung-Yeon,Oh, Hye-Jwa,Park, Hyun-Sil,Park, Min-Jung,Lim, Mi-Ae,Park, Mi-Kyung,Kim, Kyung-Woon,Cho, Mi-La,Cho, Seok-Goo Informa Healthcare 2012 Autoimmunity Vol.45 No.6

<P>Maintaining an appropriate balance between subsets of CD4<SUP>+</SUP> helper T cells and T regulatory cells (Tregs) is a critical process in immune homeostasis and a protective mechanism against autoimmunity and inflammation. To identify the role of vitamin A-related compounds, we investigated the regulation of interleukin (IL)-17-producing helper T cells (Th17 cells) and Tregs treated with all-trans-retinal (retinal). CD4<SUP>+</SUP>T cells or total cells from the spleens of C57BL/6 mice were stimulated under Treg-polarizing (anti-CD3/CD28 and TGF-β) or Th17-polarizing (anti-CD3/CD28, TGF-β, and IL-6) conditions in the presence or absence of retinal. To analyze their suppressive abilities, retinal-induced Tregs or TGF-β-induced Tregs were co-cultured with responder T cells. Collagen-induced arthritis (CIA) was established in interferon (IFN)-γ knockout mice. On day 13, retinal-induced Tregs were adoptively transferred to mice with established CIA after second immunizations. Compared with TGF-β-induced Treg cells, retinal-induced Tregs showed increased Foxp3 expression and mediated stronger suppressive activity. Under Th17-polarizing conditions, retinal inhibited the production of IL-17 and increased the expression of Foxp3.Retinal-induced Tregs showed therapeutic effects in IFN-γ knockout CIA mice. Thus, we demonstrated that retinal reciprocally regulates Foxp3<SUP>+</SUP> Tregs and Th17 cells. These findings suggest that retinal, a vitamin A metabolite, can regulate the balance between pro- and anti-inflammatory immunity. A better understanding of the manipulation of Foxp3 and Tregs may enable the application of this tremendous therapeutic potential in various autoimmune diseases.</P>

Exosomes derived from regulatory T cells attenuates MPP+-induced inflammatory response and oxidative stress in BV-2 cells by inhibiting the TLR4/NF-κB signaling

Liu Jun,Zhang Junqing,Ao Yuanyuan 대한독성 유전단백체 학회 2023 Molecular & cellular toxicology Vol.19 No.2

Background Parkinson’s disease (PD) is a common neurodegenerative disorder associated with microglia-mediated neuroinfl ammation in pathogenesis. Regulatory T cells (Treg cells) are involved in the regulation of microglia activation and neuroinfl ammation. However, it is yet to be established whether exosomes derived from Treg cells (Treg-Exos) possess protective eff ect against MPP + -induced infl ammation and oxidative stress in microglia. Objective In our study, we examined the function of Treg cells in the in vitro PD model. MTT assay was used to assess the viability of BV2 cells. ROS, MDA, and SOD activity were detected, and ELISA was performed to estimate the infl ammatory response and oxidative stress of BV-2 cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were applied to detect the level changes of genes involved in the TLR4/NF-κB signaling pathway. Results The results showed that Treg-Exos improved the cell viability of MPP + -treated BV2 cells. MPP + -induced increase in ROS and MDA production, as well as decrease in SOD activity in BV2 cells were attenuated by Treg-Exos. The increased levels of infl ammatory cytokines IL-β, IL-6, and TNF-α in MPP + -induced BV2 cells were also prevented by the treatment of Treg-Exos. Treg-Exos inhibited MPP + -induced activation of the TLR4/NF-κB signaling, indicated by decreased protein level of TLR4 and p-p65/p65 ratio in BV2 cells. Further, we also found that upregulation of TLR4 blocks the protective eff ect of Treg-Exos on MPP + -treated BV2 cells. Conclusions Collectively, Treg-Exos attenuated MPP + -induced oxidative stress and infl ammatory injury in BV-2 cells by inhibiting the TLR4/NF-κB signaling.

Canine mesenchymal stem cells immunomodulate atopic dermatitis through the induction of regulatory T cells in an ex vivo experimental study

( Jeong Su Byeon ),( Jienny Lee ),( Do Hyung Kim ),( Gyeong Been Lee ),( Hee Ryang Kim ),( Na Yeon Gu ),( In Soo Cho ),( Sang Ho Cha ) 한국예방수의학회(구 한국수의공중보건학회) 2016 예방수의학회지 Vol.40 No.1

Mesenchymal stem cells (MSCs) are multipotent stem cells, which can be induced to differentiate into several cells. MSCs are also reported to possess immunomodulatory properties through secretion of inflammatory cytokines and generation of regulatory T (Treg) cells. Treg cells play an important role in allergic disorders, including atopic dermatitis. We examined the immunomodulatory effects of canine adipose tissue derived-MSCs (cAD-MSCs) in 3 groups: Group 1, untreated normal dog; Group 2, dogs with Dermatophagoides farinae ointment-induced atopic dermatitis; and Group 3, dogs with atopic dermatitis. Canine peripheral blood mononuclear cells (PBMCs) were collected from each group and co-cultured with cAD-MSCs. After co-culturing, PBMCs were separated and the expression of Treg cells was examined by flow cytometry. According to the results, the populations of Treg cells were increased in 3 ex vivo experimental groups, co-cultured with cAD-MSCs. These results would be important for the application of MSCs in clinical trials.

인간의 말초혈액에서 염증성 사이토카인에 의한 Th17 세포의 분화에 미치는 영향

허유정 ( Yu Jung Heo ),박미경 ( Mi Kyung Park ),주지현 ( Ji Hyeon Ju ),박경수 ( Kyung Su Park ),조미라 ( Mi La Cho ),김호연 ( Ho Youn Kim ) 대한류마티스학회 2009 대한류마티스학회지 Vol.16 No.2

Objective: IL-17-producing T cells (Th17 cells) have been identified as a distinct lineage of CD4+ T helper cells in mice. Since this discovery, many efforts have been made to investigate the characteristics and the role of human Th17 cells and the factors involved in their differentiation. This study was undertaken to assess the effects of cytokines and stimulatory conditions on the differentiation of human CD4+ T cells into Th17 cells. Methods: Peripheral blood CD4+ T cells were isolated from healthy humans and then these cells were cultured with using various stimulatory conditions. The Th17 cells and regulatory T (Treg) cells were detected by flow cytometry (FACs). The related gene expressions of cytokines, transcription factors and chemokine receptors were determined by ELISA and RT-PCR. Results: In the presence of inflammatory cytokines, TNFa and IL-1b, the human CD4+ T cells rapidly produced IL-17 in response to anti-CD3/anti-CD28 stimulation, whereas, with anti-CD3/ anti-CD28 stimulation alone, the CD4+ T cells expressed low levels of IL-17. TNFa and IL-1b were also important inducers of IL-22 production. IL-6 and IL-23 up-regulated the RORgammat, CCR4 and CCR6 expressions in the human CD4+ T cells. In response to TGF-b and IL-2, the human CD4+ T cells were rapidly induced to express FoxP3, IL-10 and CCR7, as compared with anti-CD3/anti-CD28 stimulation alone. Conclusion: The effect of inflammatory cytokines on the differentiation of human Th17 cells may help us to understand their pathogenic role. Moreover, the differential expression of chemokine receptors and transcription factors of the subsets of CD4+ T cells with the different features of Th17 and Treg, may raise new issues concerning the pathogenesis of autoimmune inflammatory diseases.

TLR4-dependent effects of ISAg treatment on conventional T cell polarization in vivo

이성원,박현정,김서현,신수용,김경희,박상재,홍석만,전성호 한국통합생물학회 2019 Animal cells and systems Vol.23 No.3

We recently demonstrated that the polysaccharide component of the Korean medicinal herb Angelica gigas (immuno-stimulatory fraction of A. gigas; ISAg) induces anticancer effects in mice by activating natural killer (NK) and natural killer T (NKT) cells. However, it is unclear whether the use of ISAg in vivo can affect the differentiation of conventional T cells. Here, we investigated the effects of ISAg on the activation of conventional CD4+ and CD8+ T cells. We found that the administration of ISAg induced the polarization of CD4+ T cells toward the acquisition of the Th1 phenotype in vivo. Additionally, in mice treated with ISAg, CD8+ T cells produced more IFNγ than in control mice treated with PBS. Moreover, treatment with ISAg activated CD4+ and CD8+ T cells as well as NK and NKT cells, resulting in the secretion of Th1-type cytokines in a toll-like receptor 4 (TLR4)-dependent manner, implying that TLR4 is critical for an optimal Th1 response. Interestingly, ISAg treatment increased the number of Foxp3+ Treg cells, but not of Th2 cells, compared to control mice treated with PBS, indicating that ISAg possesses an immunomodulatory capacity that can control adaptive immune responses. Taken together, our results indicate that ISAg possesses a Th1-enhancing activity that could be used to treat Th2- mediated allergic immune diseases such as atopic dermatitis.

IL2 is required for functional maturation of regulatory T cells

전필현,오권익 한국통합생물학회 2017 Animal cells and systems Vol.21 No.1

Regulatory T cells (Tregs), specified by the expression of transcription factor Foxp3, operate Foxp3- dependent programs to maintain self-tolerance. In addition to Foxp3, other tissue-specific transcription factors are also required by Tregs to control the corresponding immune responses like follicular Tregs which express both Foxp3 and Bcl6 controlling germinal center reactions. Here, we show that Interleukin 2 (IL2) is required for the optimal expression of T helper type 1 (Th1) transcription factor T-box 21 (Tbx21, T-bet) in Tregs. The expression levels of CXCR3 and Tbet were reduced in IL2 deficient Tregs. Furthermore, IL2 deficient Treg cells failed to control the proliferation of CD4+ T cells in vitro and could not prevent the progression of colitis characterized by Th1 immune responses. Taken together, our data suggest that IL2 is essential for the functional maturation of Tregs including the optimal suppressive activity and the expression of tissue-specific transcription factors like T-bet.

Effects of Gastric Cancer Cells on the Differentiation of Treg Cells

Hu, Jing-Lan,Yang, Zhen,Tang, Jian-Rong,Fu, Xue-Qin,Yao, Lan-Jie Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.8

The aim of this study was evaluated the prevalence of Treg cells in peripheral blood in patients with gastric cancer, and investigate the effect of gastric cancer cells on their differentiation. ELISA was employed to assess the concentrations of TGF-${\beta}$ and IL-10 in gastric cancer patients' serum. Then, mouse gastric cancer cells were co-cultured with T lymphocytes or T lymphocytes + anti-TGF-${\beta}$. Flow cytometric analysis and RT-PCR were then performed to detect Treg cells and TGF-${\beta}$ and IL-10 expression in gastric cancer cells. Our data showed that the expression of TGF-${\beta}$ and IL-10 in the patients with gastric cancer was increased compared to the case with healthy donors. The population of Treg cells and the expression levels of TGF-${\beta}$ and IL-10 in the co-culture group were much higher than in the control group (18.6% vs 9.5%) (P<0.05). Moreover, the population of Treg cells and the expression levels of TGF-${\beta}$ and IL-10 in the co-culture systerm were clearly decreased after addition of anti-TGF-${\beta}$ (7.7% vs 19.6%) (P<0.01). In conclusion, gastric cancer cells may induce Treg cell differentiation through TGF-${\beta}$, and further promote immunosuppression.

Interleukin-10-Producing B Cells Help Suppress Ovariectomy-Mediated Osteoporosis

Yuhua Wang,Wei Zhang,임성민,Li Xu,진준오 대한면역학회 2020 Immune Network Vol.20 No.6

Osteoporosis is prevalent in elderly women and it may cause dental implant failure. In particular, estrogen deficiency in postmenopausal women leads to higher rates of osteoporosis prevalence. Immune cell-mediated effects involving the development of osteoporosis have been studied previously; however, the role of IL-10-producing regulatory B (B10) cells in osteoporosis is largely unclear. Here, we examined the role of B10 cells in osteoporosis. C57BL/6 mice were subjected to ovariectomy (OVX). Fifteen weeks after OVX surgery, the first molar of the right maxillary was extracted, and twenty-four weeks after OVX surgery, serous progression of osteoporosis was observed in the alveolar bone. Moreover, the proportion of CD19+CD5+CD1dhigh regulatory B cells, B10, and CD4+CD25+FoxP3+ regulatory T cells from the spleen of OVX mice decreased during the progression of osteoporosis, compared to controls. In contrast to regulatory cells, IL-17-producing Th (Th17) cell levels were increased in OVX mice. Adoptive transfer of B10 cells to OVX mice led to a decrease in Th17 cell abundance and inhibited the development of osteoporosis in the alveolar bone from OVX mice. Thus, our results suggest that B10 cells may help suppress osteoporosis development.

CD4 effector T cell differentiation is controlled by IL-15 that is expressed and presented <i>in trans</i>

Waickman, Adam T.,Ligons, Davinna L.,Hwang, SuJin,Park, Joo-Young,Lazarevic, Vanja,Sato, Noriko,Hong, Changwan,Park, Jung-Hyun Elsevier 2017 Cytokine Vol.99 No.-

<P><B>Abstract</B></P> <P>T cells are both producers and consumers of cytokines, and autocrine cytokine signaling plays a critical role in T cell immunity. IL-15 is a homeostatic cytokine for T cells that also controls inflammatory immune responses. An autocrine role of T cell-derived IL-15, however, remains unclear. Here we examined IL-15 expression and signaling upon effector T cell differentiation in mice, and, surprisingly, found that CD4 T cells did not express IL-15. CD4 T cells lacked <I>Il15</I> gene reporter activity, did not contain IL-15 transcripts, and did not produce IL-15Rα, the proprietary IL-15 receptor required for IL-15 <I>trans</I>-presentation. Moreover, IL-15 failed to inhibit Th17 cell differentiation and failed to generate Foxp3<SUP>+</SUP> Treg cells <I>in vitro</I>. IL-2, which utilizes the same IL-2Rβ/γc receptor complex, however, successfully did so. Exogenous IL-15 only exerted bioactivity and controlled T cell differentiation when it was <I>trans</I>-presented by IL-15Rα. Consequently, IL-15Rα-bound IL-15, but not free IL-15, suppressed Th17 cell differentiation and induced Treg cell generation. Collectively, these results reveal the absence of an IL-15 autocrine loop in CD4 T cells and strongly suggest that IL-15 <I>trans</I>-presentation by non-CD4 T cells is the primary mechanism via which IL-15 controls CD4 effector T cell differentiation.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Unlike most other γc cytokines, IL-15 is not produced by activated CD4 T cells. </LI> <LI> Free IL-15 phosphorylates STAT5 but does not affect CD4 T cell differentiation. </LI> <LI> IL-15Rα-bound IL-15, but not free IL-15, suppresses Th17 cell generation. </LI> <LI> IL-15 <I>trans</I>-presentation is required to control CD4 effector T cell differentiation. </LI> </UL> </P>

<i>Piper nigrum</i> extract ameliorated allergic inflammation through inhibiting Th2/Th17 responses and mast cells activation

Bui, Thi Tho,Piao, Chun Hua,Song, Chang Ho,Shin, Hee Soon,Shon, Dong-Hwa,Chai, Ok Hee Elsevier 2017 Cellular immunology Vol.322 No.-

<P><B>Abstract</B></P> <P> <I>Piper nigrum</I> (Piperaceae) is commonly used as a spice and traditional medicine in many countries. <I>P. nigrum</I> has been reported to have anti-oxidant, anti-bacterial, anti-tumor, anti-mutagenic, anti-diabetic, and anti-inflammatory properties. However, the effect of <I>P. nigrum</I> on allergic asthma has not been known. This study investigated the effect of <I>P. nigrum</I> ethanol extracts (PNE) on airway inflammation in asthmatic mice model. In the ovalbumin (OVA)-induced allergic asthma model, we analysed the number of inflammatory cells and cytokines production in bronchoalveolar lavage fluid (BALF) and lung tissue; histological structure; as well as the total immunoglobulin (Ig)E, anti-OVA IgE, anti-OVA IgG<SUB>1</SUB> and histamine levels in serum. The oral administration (200 mg/kg) of PNE reduced the accumulation of inflammatory cells (eosinophils, neutrophils in BALF and mast cells in lung tissue); regulated the balance of the cytokines production of Th1, Th2, Th17 and Treg cells, specifically, inhibited the expressions of GATA3, IL-4, IL-6, IL-1β, RORγt, IL-17A, TNF-α and increased the secretions of IL-10, INF-γ in BALF and lung homogenate. Moreover, PNE suppressed the levels of total IgE, anti-OVA IgE, anti-OVA IgG<SUB>1</SUB> and histamine release in serum. The histological analysis showed that the fibrosis and infiltration of inflammatory cells were also ameliorated in PNE treated mice. On the other hand, PNE inhibited the allergic responses via inactivation of rat peritoneal mast cells degranulation. These results suggest that PNE has therapeutic potential for treating allergic asthma through inhibiting Th2/Th17 responses and mast cells activation.</P> <P><B>Highlights</B></P> <P> <UL> <LI> The anti-allergic effect of <I>Piper nigrum</I> is examined. </LI> <LI> The mechanism bases on inhibiting Th2/Th17 responses and mast cells activation. </LI> <LI> <I>Piper nigrum</I> significantly inhibited proinflammatory cytokines and inflammatory cells. </LI> <LI> <I>Piper nigrum</I> provide a promising strategy for immunotherapy for allergic asthma treatment. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>