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>

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.

Regulatory T Cells in Tumor Microenvironment and Approach for Anticancer Immunotherapy

Jung-Ho Kim,Beom Seok Kim,이상규 대한면역학회 2020 Immune Network Vol.20 No.1

Tregs have a role in immunological tolerance and immune homeostasis by suppressing immune reactions, and its therapeutic potential is critical in autoimmune diseases and cancers. There have been multiple studies conducted on Tregs because of their roles in immune suppression and therapeutic potential. In tumor immunity, Tregs can promote the development and progression of tumors by preventing effective anti-tumor immune responses in tumor-bearing hosts. High infiltration of Tregs into tumor tissue results in poor survival in various types of cancer patients. Identifying factors specifically expressed in Tregs that affect the maintenance of stability and function of Tregs is important for understanding cancer pathogenesis and identifying therapeutic targets. Thus, manipulation of Tregs is a promising anticancer strategy, but finding markers for Treg-specific depletion and controlling these cells require fine-tuning and further research. Here, we discuss the role of Tregs in cancer and the development of Treg-targeted therapies to promote cancer immunotherapy.

Immunomodulation for Tissue Repair and Regeneration

문상준,Hong Jihye,Go Seokhyeong,Kim Byung-Soo 한국조직공학과 재생의학회 2023 조직공학과 재생의학 Vol.20 No.3

Various immune cells participate in repair and regeneration following tissue injury or damage, orchestrating tissue inflammation and regeneration processes. A deeper understanding of the immune system’s involvement in tissue repair and regeneration is critical for the development of successful reparatory and regenerative strategies. Here we review recent technologies that facilitate cell-based and biomaterial-based modulation of the immune systems for tissue repair and regeneration. First, we summarize the roles of various types of immune cells in tissue repair. Second, we review the principle, examples, and limitations of regulatory T (Treg) cell-based therapy, a representative cell-based immunotherapy. Finally, we discuss biomaterial-based immunotherapy strategies that aim to modulate immune cells using various biomaterials for tissue repair and regeneration.

Role of Regulatory Cells in Oral Tolerance

Marcin Wawrzyniak,Liam O`Mahony,Mübeccel Akdis 대한천식알레르기학회 2017 Allergy, Asthma & Immunology Research Vol.9 No.2

The immune system is continuously exposed to great amounts of different antigens from both food and intestinal microbes. Immune tolerance to these antigens is very important for intestinal and systemic immune homeostasis. Oral tolerance is a specific type of peripheral tolerance induced by exposure to antigen via the oral route. Investigations on the role of intestinal immune system in preventing hypersensitivity reactions to innocuous dietary and microbial antigens have been intensively performed during the last 2 decades. In this review article, we discuss how food allergens are recognized by the intestinal immune system and draw attention to the role of regulatory T (Treg) and B (Breg) cells in the establishment of oral tolerance and tolerogenic features of intestinal dendritic cells. We also emphasize the potential role of tonsils in oral tolerance induction because of their anatomical location, cellular composition, and possible usage to develop novel ways of specific immunotherapy for the treatment of allergic diseases.

Post-Translational Modifications in Transcription Factors that Determine T Helper Cell Differentiation

Kim, Hyo Kyeong,Jeong, Mi Gyeong,Hwang, Eun Sook Korean Society for Molecular and Cellular Biology 2021 Molecules and cells Vol.44 No.5

CD4+ T helper (Th) cells play a crucial role in the modulation of innate and adaptive immune responses through the differentiation of Th precursor cells into several subsets, including Th1, Th2, Th17, and regulatory T (Treg) cells. Effector Th and Treg cells are distinguished by the production of signature cytokines and are important for eliminating intracellular and extracellular pathogens and maintaining immune homeostasis. Stimulation of naive Th cells by T cell receptor and specific cytokines activates master transcription factors and induces lineage specification during the differentiation of Th cells. The master transcription factors directly activate the transcription of signature cytokine genes and also undergo post-translational modifications to fine-tune cytokine production and maintain immune balance through cross-regulation with each other. This review highlights the post-translational modifications of master transcription factors that control the differentiation of effector Th and Treg cells and provides additional insights on the immune regulation mediated by protein argininemodifying enzymes in effector Th cells.

Regulatory T Cells in Tumor Microenvironment and Approach for Anticancer Immunotherapy

Jung-Ho Kim,Beom Seok Kim,Sang-Kyou Lee 대한면역학회 2020 Immune Network Vol.20 No.1

Autoimmune Hepatic Failure Following Acute Hepatitis A is Accompanied by Inflammatory Conversion of Regulatory T Cells

임가람,김범경,신의철,박준용 연세대학교의과대학 2020 Yonsei medical journal Vol.61 No.1

To evaluate the pathophysiology of autoimmune hepatitis (AIH) following acute hepatitis A (AHA) in immunologic aspects, weperformed multi-color flow cytometry with peripheral blood mononuclear cells of a patient who underwent liver transplantationdue to AIH-induced liver failure. Unlike general AHA patients, the proportion of tumor necrosis factor-α-producing Treg cells remainedhigh for 6 months after diagnosis of AHA until she underwent a liver transplantation. The conversion of Treg cells intomediators of inflammation may have played a role in the autoimmune pathogenesis following AHA.

Dab2, a negative regulator of DC immunogenicity, is an attractive molecular target for DC-based immunotherapy.

Ahmed, Md Selim,Byeon, Se Eun,Jeong, Yideul,Miah, Mohammad Alam,Salahuddin, Md,Lee, Yoon,Park, Sung-Soo,Bae, Yong-Soo Landes Bioscience 2015 Oncoimmunology Vol.4 No.1

<P>Dab2 is an adapter protein involved in receptor-mediated signaling, endocytosis, cell adhesion, hematopoietic cell differentiation, and angiogenesis. It plays a pivotal role in controlling cellular homeostasis. In the immune system, the Dab2 is a Foxp3 target gene and is required for regulatory T (Treg) cell function. Dab2 expression and its biological function in dendritic cells (DCs) have not been described. In this study, we found that Dab2 was significantly induced during the development of mouse bone marrow (BM)-derived DCs (BMDCs) and human monocyte-derived DCs (MoDCs). Even in a steady state, Dab2 was expressed in mouse splenic DCs (spDCs). STAT5 activation, Foxp3 expression, and hnRNPE1 activation mediated by PI3K/Akt signaling were required for Dab2 expression during GM-CSF-derived BMDC development regardless of TGF-β signaling. Dab2-silencing was accompanied by enhanced IL-12 and IL-6 expression, and an improved capacity of DC for antigen uptake, migration and T cell stimulation, which generated strong CTL in vaccinated mice. Vaccination with Dab2-silenced DCs inhibited tumor growth more effectively than did vaccination with wild type DCs. Dab2-overexpression abrogated the efficacy of the DC vaccine in DC-based tumor immunotherapy. These data strongly suggest that Dab2 might be an intrinsic negative regulator of the immunogenicity of DCs, thus might be an attractive molecular target to improve DC vaccine efficacy.</P>

Comparison of Administration Routes on the Protective Effects of Bee Venom Phospholipase A2 in a Mouse Model of Parkinson’s Disease

Baek, Hyunjung,Jang, Hyun Il,Jeon, Hat Nim,Bae, Hyunsu Frontiers Media S.A. 2018 FRONTIERS IN AGING NEUROSCIENCE Vol.10 No.-

<P>Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide. Progressive loss of dopaminergic neurons in the substantia nigra (SN) and their synaptic terminal connections in the striatum are main characterizations of PD. Although many efforts have been made to develop therapeutics, no treatment has been proven effective. We previously demonstrated that bvPLA2 can protect dopaminergic neurons by modulating neuroinflammatory responses in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced mouse model of PD. The cellular basis for the neuroprotective response of bvPLA2 was the induction of CD4<SUP>+</SUP>CD25<SUP>+</SUP> regulatory T cells (Tregs), a population known to suppress immune activation and maintain homeostasis and tolerance to self-antigen. The aim of the present study was to investigate the effects of different routes of bvPLA2 administration in a PD mouse model. Neurobehavioral assessment revealed progressive deterioration in locomotor functions of the MPTP group compared with the control group. However, such functions were improved following subcutaneous (s.c.) bvPLA2 administration. The results showed that the s.c. route of bvPLA2 administration contributed to the induction of Treg cells and the reduction of Th1 and Th17 populations, demonstrating that the neuroprotective effects were associated with reduced tyrosine hydroxylase (TH)-positive dopaminergic neurons and microglia. These results suggested that the s.c. bvPLA2 injection could be beneficial for treating aspects of PD.</P>