scholarly journals Essential functions of Runx/Cbfβ in gut conventional dendritic cells for priming Rorγt+ T cells

2019 ◽  
Vol 3 (1) ◽  
pp. e201900441 ◽  
Author(s):  
Mari Tenno ◽  
Alicia Yoke Wei Wong ◽  
Mika Ikegaya ◽  
Eiji Miyauchi ◽  
Wooseok Seo ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Cell Polarization ◽  
Th Cells ◽  
Th Cell ◽  
Intrinsic Mechanism ◽  
Specific Effector ◽  
Acquired Immune Responses ◽  
Type 3

Acquired immune responses are initiated by activation of CD4+ helper T (Th) cells via recognition of antigens presented by conventional dendritic cells (cDCs). DCs instruct Th-cell polarization program into specific effector Th subset, which will dictate the type of immune responses. Hence, it is important to unravel how differentiation and/or activation of DC are linked with Th-cell–intrinsic mechanism that directs differentiation toward a specific effector Th subset. Here, we show that loss of Runx/Cbfβ transcription factors complexes during DC development leads to loss of CD103+CD11b+ cDC2s and alters characteristics of CD103−CD11b+ cDCs in the intestine, which was accompanied with impaired differentiation of Rorγt+ Th17 cells and type 3 Rorγt+ regulatory T cells. We also show that a Runx-binding enhancer in the Rorc gene is essential for T cells to integrate cDC-derived signals to induce Rorγt expression. These findings reveal that Runx/Cbfβ complexes play crucial and complementary roles in cDCs and Th cells to shape converging type 3 immune responses.

scholarly journals Interferon Regulatory Factor 4 Is a Key Factor in Regulation of Thelper Cell Polarization in Graft-Versus-Host Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3313-3313
Author(s):  
Jochen T Frueh ◽  
Bushra Rais ◽  
Daniele Yumi Sunaga-Franze ◽  
Katja Stein ◽  
Sascha Sauer ◽  
...  
Keyword(s):  
T Cells ◽  
Treg Cells ◽  
Cell Polarization ◽  
Th Cells ◽  
Th Cell ◽  
Target Organs ◽  
Donor T Cells ◽  
Interferon Regulatory Factor 4

Abstract Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for severe malignant diseases. Following allo-HSCT, donor T cells are the driving force for eradication of the remaining malignant cells known as graft-versus-tumor (GVT) effect. However, these alloreactive T cells are also responsible for induction of graft-versus-host disease (GVHD). To date, the role of the different Thelper (Th) subsets in the pathogenesis of GVHD is not completely understood. Interestingly, these subsets share expression of a transcription factor called Interferon Regulatory Factor 4 (IRF4), which is proposed as a master regulator of cell fate decision of T cells. This project aims to analyze the role of IRF4 in Th cell polarization during the development of GVHD. Methods: In mixed lymphocyte reaction (MLR), we analyzed the proliferation capacity of CFSE-labelled IRF4-deficient (IRF4-/-) T cells upon allogeneic stimulation by LPS-induced dendritic cells (DC). For analyzing the impact of IRF4 in vivo, we used previously published complete MHC-mismatched murine GVHD model (Ullrich et al., J Clin Invest, 2018). Herein, we investigated the alloreactivity of the transplanted donor T cells towards GVHD target organs with focus on colonic tissue. Additionally, RNA sequencing of re-isolated and high purity FACS-sorted donor Th cells were performed to get a deep insight into the IRF4-mediated regulation of Th cell polarization. Results: In the MLR setting, reduced CFSE dilution indicated a diminished proliferative capacity of both CD4+ and CD8+ IRF4-/- T cells compared to the corresponding WT (IRF4+/+) T cell subsets upon allogeneic stimulation (Figure 1A). Furthermore, while alloreactive WT CD4+ T cells induced severe forms of GVHD in vivo, clinical GVHD symptoms of recipients transplanted with IRF4-/- CD4+ T cells were significantly reduced and these mice showed prolonged overall survival (Figure 1B). Analyzing the mechanism, we found that the frequency of in vivo circulating donorCD4+ IRF4-/- T cells was reduced compared to transplanted WT Th cells, especially in the GVHD target organs such as the colon. However, IRF4-/- Th cells persisted in spleen, lung and colon even if they showed a reduced proliferative capacity. In line with that, colonoscopy of mice transplanted with IRF4-deficient Th cells revealed a significant reduction of GVHD associated colitis. Transcriptome analysis of re-isolated and high purity FACS-sorted donor Th cells depicted an altered gene expression profile in donor IRF4-/- Th cells compared to donor WT Th cells. Specifically, master regulators of Th cell subsets like T-bet (Th1), RORγt (Th17) and to some amount also GATA-3 (Th2) were downregulated in donor IRF4-/- Th cells whereas FoxP3, the master regulator of regulatory T cells (Treg cells), was significantly upregulated. Along the same line cytokines associated with Th1, Th2 and Th17 cell subsets such as IFN-γ, IL-21, IL-6 and IL-13 were also significantly downregulated. Besides genes that are associated with Treg cell function like Helios, FR4 (folate receptor 4) and Neuropilin 1, a transcriptional repressor, Bach2, which regulates the formation of Treg cells and suppresses Th1, Th2 and Th17 subset differentiation was highly upregulated (Tsukumo et al., Proc Natl Acad Sci U S A, 2013; Kim et al., J Immunol, 2014 ; Roychoudhuri et al., Nature, 2013 ; Vahedi et al., Nature, 2015). Along with the upregulation of Bach2 and the significant downregulation of Blimp1, another transcriptional repressor involved in T cell homeostasis and function as well as direct target of Bach2, we hypothesize that IRF4 might compete with BACH2 for the binding to BATF. These hypotheses also rely on our previous finding of BATF as critical mediator of GVHD colitis and are currently under further evaluation (Ullrich et al., J Clin Invest, 2018). Conclusion: In summary, our results indicate that IRF4 plays a key role in regulation of the Th cell polarization and therefore also in the development of GVHD. Thus, IRF4 in its interplay with BATF might be considered as a clinically relevant target for GVHD therapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Dendritic Cells Promoted by Ginseng Saponins Drive a Potent Th1 Polarization

2008 ◽  
Vol 3 ◽  
pp. BMI.S585 ◽  
Author(s):  
Masao Takei ◽  
Eiichi Tachikawa ◽  
Akemi Umeyama
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cell Polarization ◽  
Th1 Cells ◽  
Human Monocytes ◽  
Ifn Γ ◽  
Pharmacologically Active ◽  
Dc Maturation

Dendritic cells (DC) play a pivotal role in the initiation of T-cell-mediated immune responses, making them an attractive cellular adjuvant for use in cancer vaccines. The interaction of T cells with DC is crucial for directing T cell differentiation towards the Th1, Th2 or Th17 type, and several factors determining the direction of the T cell polarization. IL-12 plays a central role in the immune system, not only by augmenting the cytotoxic activity of T cells and NK cells and regulating IFN-γ production, but also by the capacity of IL-12 to promote the development of Th1 cells. Therefore, it is important to identify factors that might affect the differentiation, maturation and function of DC. Ginseng is a medicinal herb widely used in Asian countries, and many of its pharmacological actions are attributed to the ginsenosides. Moreover, T-cadinol and calamenene are sesquterpenes isolated from the heartwood of Cryptomeria japonica being pharmacologically active substances. We investigated whether M1 and M4, end products of steroidal ginseng saponins metabolized in digestive tracts, as well as T-cadinol and calamenene can drive DC maturation from human monocytes in vitro. Human monocytes were cultured with GM-CSF and IL-4 for 6 days under standard conditions, followed by another 2 days in the presence of M1, M4, T-cadinol or calamenene. The expression levels of CD1a, CD80, CD83, CD86 and HLA-DR on M1-primed DC, M4-primed DC, T-cadinol-primed DC and calamenene-primed DC were enhanced with a concomitant decrease in endocytic activity. M1-primed DC, M4-primed DC, T-cadinol-primed DC or calamenene-primed DC enhanced the T cell stimulatory capacity in an allo MLR (allogeneic mixed lymphocyte reaction). Naïve T cells co-cultured with allogeneic M1-primed DC, M4-primed DC, T-cadinol-primed DC or calamenene-primed DC turned into typical Th1 cells, which produced large quantities of IFN-γ and released small amounts of IL-4 depending on IL-12 secretion. In the CTL assay (cytotoxic T-lymphocyte assay), the production of IFN-γ and 51Cr release on M4-primed DC was more augmented than of immature DC or TNF-α-primed DC. These results suggest that M1, M4, T-cadinol and calamenene appear to be a good factor to induce DC maturation, or even better in some respect, for the use in clinical DC therapy to induce strong Th1 type immune responses.

scholarly journals Rho-mDia1 pathway is required for adhesion, migration, and T-cell stimulation in dendritic cells

Blood ◽  
2010 ◽  
Vol 116 (26) ◽  
pp. 5875-5884 ◽  
Author(s):  
Hideaki Tanizaki ◽  
Gyohei Egawa ◽  
Kayo Inaba ◽  
Tetsuya Honda ◽  
Saeko Nakajima ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Lymph Nodes ◽  
Actin Polymerization ◽  
Cell Stimulation ◽  
T Cell Stimulation ◽  
Acquired Immune Responses

Abstract Dendritic cells (DCs) are essential for the initiation of acquired immune responses through antigen acquisition, migration, maturation, and T-cell stimulation. One of the critical mechanisms in this response is the process actin nucleation and polymerization, which is mediated by several groups of proteins, including mammalian Diaphanous-related formins (mDia). However, the role of mDia in DCs remains unknown. Herein, we examined the role of mDia1 (one of the isoforms of mDia) in DCs. Although the proliferation and maturation of bone marrow-derived DCs were comparable between control C57BL/6 and mDia1-deficient (mDia1−/−) mice, adhesion and spreading to cellular matrix were impaired in mDia1−/− bone marrow–derived DCs. In addition, fluorescein isothiocyanate-induced cutaneous DC migration to draining lymph nodes in vivo and invasive migration and directional migration to CCL21 in vitro were suppressed in mDia1−/− DCs. Moreover, sustained T-cell interaction and T-cell stimulation in lymph nodes were impaired by mDia1 deficiency. Consistent with this, the DC-dependent delayed hypersensitivity response was attenuated by mDia1-deficient DCs. These results suggest that actin polymerization, which is mediated by mDia1, is essential for several aspects of DC-initiated acquired immune responses.

Efficient migration of dendritic cells toward lymph node chemokines and induction of TH1 responses require maturation stimulus and apoptotic cell interaction

Blood ◽  
2005 ◽  
Vol 106 (5) ◽  
pp. 1734-1741 ◽  
Author(s):  
Nicolas Bertho ◽  
Henri Adamski ◽  
Louis Toujas ◽  
Martine Debove ◽  
Jean Davoust ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Lymph Node ◽  
Immune Responses ◽  
Tumor Cells ◽  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Tnf Α

Abstract Dendritic cells (DCs) have the unique ability to initiate primary immune responses, and they can be conditioned for vaccinal purposes to present antigens after the engulfment of apoptotic cells. To recruit the rare antigen-specific naive T cells, DCs require a maturation step and subsequent transport toward lymph node (LN). To date, prostaglandin E2 (PGE2) is the best-characterized compound inducing this LN-directed migration in vitro, but PGE2 may skew the immune responses in a TH2 direction. We demonstrate here that on incubation with apoptotic tumor cells and tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS), human monocyte-derived DCs become fully mature and acquire high migratory capacities toward LN-directing chemokines. The migration of TNF-α-treated DCs occurs only after cotreatment with apoptotic cells but not with necrotic cells. DC migration requires CD36 expression and incubation with apoptotic cells in the presence of heat-labile serum components. Moreover, on treatment with apoptotic cells and LPS, the migrating DCs are able to recruit naive T cells to generate TH1 immune responses. Our results show that the cotreatment of DCs with apoptotic tumor cells and inflammatory signals is promising for the design of an antitumoral DC-based vaccine. (Blood. 2005;106:1734-1741)

scholarly journals Expanded circulating follicular dendritic cells facilitate immune responses in chronic HBV infection

2020 ◽  
Author(s):  
Xiaoyi Li ◽  
Qifan Zhang ◽  
Wanyue Zhang ◽  
Guofu Ye ◽  
Yanchen Ma ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
B Cells ◽  
Hepatitis B ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Hbv Infection ◽  
Follicular Dendritic Cells ◽  
Chronic Hbv Infection ◽  
Chronic Hbv

Abstract Background: The restoration of host hepatitis B virus (HBV)-specific antiviral immunity is an effective strategy for hepatitis B recovery. Follicular dendritic cells (FDCs) play a crucial role in immune regulation. The goal of the present study was to investigate the characteristics and functions of FDCs in chronic HBV infection. Methods: The frequencies of FDCs in peripheral blood, liver, and spleen were measured in patients with chronic HBV infection. Isolated FDCs from splenic tissues of HBV-related liver cirrhosis-induced hypersplenism patients were cultured with autologous intrasplenic CD4 + T cells and CD19 + B cells.Results: We found that patients with chronic HBV infection had a significantly increased frequency of circulating FDCs compared with that of healthy controls. Additionally, the frequency of circulating FDCs was positively correlated with that of intrahepatic and intrasplenic counterparts. Moreover, a positive correlation between the frequency of circulating FDCs and plasmablast and memory B cells, as well as C-X-C motif chemokine receptor type 5 (CXCR5) + CD4 + T cells and CXCR5 + CD8 + T cells was also observed. Notably, in vitro experiments demonstrated that FDCs derived from splenic tissues of chronic HBV patients facilitated interferon-γ and interleukin-21 production from autologous intrasplenic CD4 + T cells and promoted the proliferation of autologous intrasplenic CD19 + B cells. Conclusions: Expanded FDCs in patients with chronic HBV infection may favor the host immune responses against HBV. The identification of this unique population may contribute to a better understanding of the immune regulatory mechanisms and provide a potential immunotherapeutic target in chronic HBV infection.

scholarly journals Evaluation of Feline Monocyte-Derived Dendritic Cells Loaded with Internally Inactivated Virus as a Vaccine against Feline Immunodeficiency Virus

2008 ◽  
Vol 15 (3) ◽  
pp. 452-459 ◽  
Author(s):  
Giulia Freer ◽  
Donatella Matteucci ◽  
Paola Mazzetti ◽  
Francesca Tarabella ◽  
Valentina Catalucci ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Immune Functions ◽  
Peripheral Blood Mononuclear ◽  
Challenge Virus ◽  
Homologous Virus ◽  
Antibody Titers ◽  
Cellular Immune ◽  
Antigen Presenting

ABSTRACT Dendritic cells are the only antigen-presenting cells that can present exogenous antigens to both helper and cytolytic T cells and prime Th1-type or Th2-type cellular immune responses. Given their unique immune functions, dendritic cells are considered attractive “live adjuvants” for vaccination and immunotherapy against cancer and infectious diseases. The present study was carried out to assess whether the reinjection of autologous monocyte-derived dendritic cells loaded with an aldithriol-2-inactivated primary isolate of feline immune deficiency virus (FIV) was able to elicit protective immune responses against the homologous virus in naive cats. Vaccine efficacy was assessed by monitoring immune responses and, finally, by challenge with the homologous virus of vaccinated, mock-vaccinated, and healthy cats. The outcome of challenge was followed by measuring cellular and antibody responses and viral and proviral loads and quantitating FIV by isolation and a count of CD4+/CD8+ T cells in blood. Vaccinated animals exhibited clearly evident FIV-specific peripheral blood mononuclear cell proliferation and antibody titers in response to immunization; however, they became infected with the challenge virus at rates comparable to those of control animals.

scholarly journals Human Dendritic Cells: Ontogeny and Their Subsets in Health and Disease

2018 ◽  
Vol 6 (4) ◽  
pp. 88 ◽  
Author(s):  
Sandra Solano-Gálvez ◽  
Sonia Tovar-Torres ◽  
María Tron-Gómez ◽  
Ariane Weiser-Smeke ◽  
Diego Álvarez-Hernández ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Current Knowledge ◽  
Lymphoid Organ ◽  
Heterogeneous Population ◽  
Health And Disease ◽  
Human Dendritic Cells ◽  
Activation Status

Dendritic cells (DCs) are a type of cells derived from bone marrow that represent 1% or less of the total hematopoietic cells of any lymphoid organ or of the total cell count of the blood or epithelia. Dendritic cells comprise a heterogeneous population of cells localized in different tissues where they act as sentinels continuously capturing antigens to present them to T cells. Dendritic cells are uniquely capable of attracting and activating naïve CD4+ and CD8+ T cells to initiate and modulate primary immune responses. They have the ability to coordinate tolerance or immunity depending on their activation status, which is why they are also considered as the orchestrating cells of the immune response. The purpose of this review is to provide a general overview of the current knowledge on ontogeny and subsets of human dendritic cells as well as their function and different biological roles.

scholarly journals Dendritic Cells/Macrophages-Targeting Feature of Ebola Glycoprotein and its Potential as Immunological Facilitator for Antiviral Vaccine Approach

2019 ◽  
Vol 7 (10) ◽  
pp. 402
Author(s):  
Titus Abiola Olukitibi ◽  
Zhujun Ao ◽  
Mona Mahmoudi ◽  
Gary A. Kobinger ◽  
Xiaojian Yao
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Ebola Virus ◽  
Vaccine Development ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Immunological Approach ◽  
Vaccine Approach ◽  
Acquired Immune Responses ◽  
Diverse Virus

In the prevention of epidemic and pandemic viral infection, the use of the antiviral vaccine has been the most successful biotechnological and biomedical approach. In recent times, vaccine development studies have focused on recruiting and targeting immunogens to dendritic cells (DCs) and macrophages to induce innate and adaptive immune responses. Interestingly, Ebola virus (EBOV) glycoprotein (GP) has a strong binding affinity with DCs and macrophages. Shreds of evidence have also shown that the interaction between EBOV GP with DCs and macrophages leads to massive recruitment of DCs and macrophages capable of regulating innate and adaptive immune responses. Therefore, studies for the development of vaccine can utilize the affinity between EBOV GP and DCs/macrophages as a novel immunological approach to induce both innate and acquired immune responses. In this review, we will discuss the unique features of EBOV GP to target the DC, and its potential to elicit strong immune responses while targeting DCs/macrophages. This review hopes to suggest and stimulate thoughts of developing a stronger and effective DC-targeting vaccine for diverse virus infection using EBOV GP.

scholarly journals Regulation of Antitumor Immune Responses by the IL-12 Family Cytokines, IL-12, IL-23, and IL-27

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Mingli Xu ◽  
Izuru Mizoguchi ◽  
Noriko Morishima ◽  
Yukino Chiba ◽  
Junichiro Mizuguchi ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Th17 Cells ◽  
Antitumor Immunity ◽  
Inflammatory Responses ◽  
Memory T Cells ◽  
Th1 Cells ◽  
Signal Transducers ◽  
Th Cell ◽  
Antigen Presenting

The interleukin (IL)-12 family, which is composed of heterodimeric cytokines including IL-12, IL-23, and IL-27, is produced by antigen-presenting cells such as macrophages and dendritic cells and plays critical roles in the regulation of helper T (Th) cell differentiation. IL-12 induces IFN- production by NK and T cells and differentiation to Th1 cells. IL-23 induces IL-17 production by memory T cells and expands and maintains inflammatory Th17 cells. IL-27 induces the early Th1 differentiation and generation of IL-10-producing regulatory T cells. In addition, these cytokines induce distinct immune responses to tumors. IL-12 activates signal transducers and activator of transcription (STAT)4 and enhances antitumor cellular immunity through interferon (IFN)- production. IL-27 activates STAT1, as does IFN- and STAT3 as well, and enhances antitumor immunity by augmenting cellular and humoral immunities. In contrast, although exogenously overexpressed IL-23 enhances antitumor immunity via memory T cells, endogenous IL-23 promotes protumor immunity through STAT3 activation by inducing inflammatory responses including IL-17 production.

Sign in / Sign up

Export Citation Format

Share Document