scholarly journals Tolerogenic function of Blimp-1 in dendritic cells

2011 ◽  
Vol 208 (11) ◽  
pp. 2193-2199 ◽  
Author(s):  
Sun Jung Kim ◽  
Yong Rui Zou ◽  
Jordan Goldstein ◽  
Boris Reizis ◽  
Betty Diamond
Keyword(s):  
Dendritic Cells ◽  
Memory Function ◽  
Critical Role ◽  
Disease Process ◽  
Effector Memory ◽  
Tfh Cells ◽  
Dc Function ◽  
Tolerogenic Function

Blimp-1 has been identified as a key regulator of plasma cell differentiation in B cells and effector/memory function in T cells. We demonstrate that Blimp-1 in dendritic cells (DCs) is required to maintain immune tolerance in female but not male mice. Female mice lacking Blimp-1 expression in DCs (DCBlimp-1ko) or haploid for Blimp-1 expression exhibit normal DC development but an altered DC function and develop lupus-like autoantibodies. Although DCs have been implicated in the pathogenesis of lupus, a defect in DC function has not previously been shown to initiate the disease process. Blimp-1ko DCs display increased production of IL-6 and preferentially induce differentiation of follicular T helper cells (TFH cells) in vitro. In vivo, the expansion of TFH cells is associated with an enhanced germinal center (GC) response and the development of autoreactivity. These studies demonstrate a critical role for Blimp-1 in the tolerogenic function of DCs and show that a diminished expression of Blimp-1 in DCs can result in aberrant activation of the adaptive immune system with the development of a lupus-like serology in a gender-specific manner. This study is of particular interest because a polymorphism of Blimp-1 associates with SLE.

Endothelial stroma programs hematopoietic stem cells to differentiate into regulatory dendritic cells through IL-10

Blood ◽  
2006 ◽  
Vol 108 (4) ◽  
pp. 1189-1197 ◽  
Author(s):  
Hua Tang ◽  
Zhenhong Guo ◽  
Minghui Zhang ◽  
Jianli Wang ◽  
Guoyou Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Hematopoietic Stem Cells ◽  
Critical Role ◽  
Regulatory Function ◽  
Hematopoietic Stem ◽  
Regulatory Dendritic Cells

Abstract Regulatory dendritic cells (DCs) have been reported recently, but their origin is poorly understood. Our previous study demonstrated that splenic stroma can drive mature DCs to proliferate and differentiate into regulatory DCs, and their natural counterpart with similar regulatory function in normal spleens has been identified. Considering that the spleen microenvironment supports hematopoiesis and that hematopoietic stem cells (HSCs) are found in spleens of adult mice, we wondered whether splenic microenvironment could differentiate HSCs into regulatory DCs. In this report, we demonstrate that endothelial splenic stroma induce HSCs to differentiate into a distinct regulatory DC subset with high expression of CD11b but low expression of Ia. CD11bhiIalo DCs secreting high levels of TGF-β, IL-10, and NO can suppress T-cell proliferation both in vitro and in vivo. Furthermore, CD11bhiIalo DCs have the ability to potently suppress allo-DTH in vivo, indicating their preventive or therapeutic perspectives for some immunologic disorders. The inhibitory function of CD11bhiIalo DCs is mediated through NO but not through induction of regulatory T (Treg) cells or T-cell anergy. IL-10, which is secreted by endothelial splenic stroma, plays a critical role in the differentiation of the regulatory CD11bhiIalo DCs from HSCs. These results suggest that splenic microenvironment may physiologically induce regulatory DC differentiation in situ.

scholarly journals Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A

2015 ◽  
Vol 112 (13) ◽  
pp. 4080-4085 ◽  
Author(s):  
Lauren P. Schewitz-Bowers ◽  
Philippa J. P. Lait ◽  
David A. Copland ◽  
Ping Chen ◽  
Wenting Wu ◽  
...  
Keyword(s):  
T Cells ◽  
Cyclosporine A ◽  
Th17 Cells ◽  
Critical Role ◽  
Adaptive Immune Response ◽  
Steroid Resistance ◽  
Effector Memory ◽  
Genome Wide

Glucocorticoids remain the cornerstone of treatment for inflammatory conditions, but their utility is limited by a plethora of side effects. One of the key goals of immunotherapy across medical disciplines is to minimize patients’ glucocorticoid use. Increasing evidence suggests that variations in the adaptive immune response play a critical role in defining the dose of glucocorticoids required to control an individual’s disease, and Th17 cells are strong candidate drivers for nonresponsiveness [also called steroid resistance (SR)]. Here we use gene-expression profiling to further characterize the SR phenotype in T cells and show that Th17 cells generated from both SR and steroid-sensitive individuals exhibit restricted genome-wide responses to glucocorticoids in vitro, and that this is independent of glucocorticoid receptor translocation or isoform expression. In addition, we demonstrate, both in transgenic murine T cells in vitro and in an in vivo murine model of autoimmunity, that Th17 cells are reciprocally sensitive to suppression with the calcineurin inhibitor, cyclosporine A. This result was replicated in human Th17 cells in vitro, which were found to have a conversely large genome-wide shift in response to cyclosporine A. These observations suggest that the clinical efficacy of cyclosporine A in the treatment of SR diseases may be because of its selective attenuation of Th17 cells, and also that novel therapeutics, which target either Th17 cells themselves or the effector memory T-helper cell population from which they are derived, would be strong candidates for drug development in the context of SR inflammation.

scholarly journals Murine Dendritic Cells Pulsed In Vitro withToxoplasma gondii Antigens Induce Protective Immunity In Vivo

1998 ◽  
Vol 66 (10) ◽  
pp. 4867-4874 ◽  
Author(s):  
Isabelle Bourguin ◽  
Muriel Moser ◽  
Dominique Buzoni-Gatel ◽  
Françoise Tielemans ◽  
Daniel Bout ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Cellular Response ◽  
Critical Role ◽  
Cell Subset ◽  
Surface Protein ◽  
Interleukin 12 ◽  
Pulsed Dc ◽  
Microneme Protein

ABSTRACT The activation of a predominant T-helper-cell subset plays a critical role in disease resolution. In the case of Toxoplasma gondii, the available evidence indicates that CD4+protective cells belong to the Th1 subset. The aim of this study was to determine whether T. gondii antigens (in T. gondii sonicate [TSo]) presented by splenic dendritic cells (DC) were able to induce a specific immune response in vivo and to protect CBA/J mice orally challenged with T. gondiicysts. CBA/J mice immunized with TSo-pulsed DC exhibited significantly fewer cysts in their brains after oral infection with T. gondii 76K than control mice did. Protected mice developed a strong humoral response in vivo, with especially high levels of anti-TSo immunoglobulin G2a antibodies in serum. T. gondii antigens such as SAG1 (surface protein), SAG2 (surface protein), MIC1 (microneme protein), ROP2 through ROP4 (rhoptry proteins), and MIC2 (microneme protein) were recognized predominantly. Furthermore, DC loaded with TSo, which synthesized high levels of interleukin-12 (IL-12), triggered a strong cellular response in vivo, as assessed by the proliferation of lymph node cells in response to TSo restimulation in vitro. Cellular proliferation was associated with gamma interferon and IL-2 production. Taken together, these results indicate that immunization of CBA/J mice with TSo-pulsed DC can induce both humoral and Th1-like cellular immune responses and affords partial resistance against the establishment of chronic toxoplasmosis.

scholarly journals Immature Dendritic Cells Phagocytose Apoptotic Cells via αvβ5 and CD36, and Cross-present Antigens to Cytotoxic T Lymphocytes

1998 ◽  
Vol 188 (7) ◽  
pp. 1359-1368 ◽  
Author(s):  
Matthew L. Albert ◽  
S.Frieda A. Pearce ◽  
Loise M. Francisco ◽  
Birthe Sauter ◽  
Pampa Roy ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Critical Role ◽  
Immature Stage ◽  
Apoptotic Cells ◽  
Cross Tolerance ◽  
Phagocytic Capacity ◽  
Immature Dendritic Cells ◽  
Antigenic Material

Dendritic cells, but not macrophages, efficiently phagocytose apoptotic cells and cross-present viral, tumor, and self-antigens to CD8+ T cells. This in vitro pathway corresponds to the in vivo phenomena of cross-priming and cross-tolerance. Here, we demonstrate that phagocytosis of apoptotic cells is restricted to the immature stage of dendritic cell (DC) development, and that this process is accompanied by the expression of a unique profile of receptors, in particular the αvβ5 integrin and CD36. Upon maturation, these receptors and, in turn, the phagocytic capacity of DCs, are downmodulated. Macrophages engulf apoptotic cells more efficiently than DCs, and although they express many receptors that mediate this uptake, they lack the αvβ5 integrin. Furthermore, in contrast to DCs, macrophages fail to cross-present antigenic material contained within the engulfed apoptotic cells. Thus, DCs use unique pathways for the phagocytosis, processing, and presentation of antigen derived from apoptotic cells on class I major histocompatibility complex. We suggest that the αvβ5 integrin plays a critical role in the trafficking of exogenous antigen by immature DCs in this cross-priming pathway.

scholarly journals Krüppel-like factor KLF10 regulates transforming growth factor receptor II expression and TGF-β signaling in CD8+ T lymphocytes

2015 ◽  
Vol 308 (5) ◽  
pp. C362-C371 ◽  
Author(s):  
Konstantinos A. Papadakis ◽  
James Krempski ◽  
Jesse Reiter ◽  
Phyllis Svingen ◽  
Yuning Xiong ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Effector Memory ◽  
Antiviral Immune Response ◽  
Ifn Γ ◽  
Tgf Β1

KLF10 has recently elicited significant attention as a transcriptional regulator of transforming growth factor-β1 (TGF-β1) signaling in CD4+ T cells. In the current study, we demonstrate a novel role for KLF10 in the regulation of TGF-β receptor II (TGF-βRII) expression with functional relevance in antiviral immune response. Specifically, we show that KLF10-deficient mice have an increased number of effector/memory CD8+ T cells, display higher levels of the T helper type 1 cell-associated transcription factor T-bet, and produce more IFN-γ following in vitro stimulation. In addition, KLF10−/− CD8+ T cells show enhanced proliferation in vitro and homeostatic proliferation in vivo. Freshly isolated CD8+ T cells from the spleen of adult mice express lower levels of surface TGF-βRII (TβRII). Congruently, in vitro activation of KLF10-deficient CD8+ T cells upregulate TGF-βRII to a lesser extent compared with wild-type (WT) CD8+ T cells, which results in attenuated Smad2 phosphorylation following TGF-β1 stimulation compared with WT CD8+ T cells. Moreover, we demonstrate that KLF10 directly binds to the TGF-βRII promoter in T cells, leading to enhanced gene expression. In vivo viral infection with Daniel's strain Theiler's murine encephalomyelitis virus (TMEV) also led to lower expression of TGF-βRII among viral-specific KLF10−/− CD8+ T cells and a higher percentage of IFN-γ-producing CD8+ T cells in the spleen. Collectively, our data reveal a critical role for KLF10 in the transcriptional activation of TGF-βRII in CD8+ T cells. Thus, KLF10 regulation of TGF-βRII in this cell subset may likely play a critical role in viral and tumor immune responses for which the integrity of the TGF-β1/TGF-βRII signaling pathway is crucial.

scholarly journals Plasmacytoid dendritic cells cross-prime naive CD8 T cells by transferring antigen to conventional dendritic cells through exosomes

2020 ◽  
Vol 117 (38) ◽  
pp. 23730-23741 ◽  
Author(s):  
Chunmei Fu ◽  
Peng Peng ◽  
Jakob Loschko ◽  
Li Feng ◽  
Phuong Pham ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd8 T Cells ◽  
Critical Role ◽  
Plasmacytoid Dendritic Cells ◽  
Viral Immunity ◽  
Cell Immunity ◽  
Antigen Transfer

Although plasmacytoid dendritic cells (pDCs) have been shown to play a critical role in generating viral immunity and promoting tolerance to suppress antitumor immunity, whether and how pDCs cross-prime CD8 T cells in vivo remain controversial. Using a pDC-targeted vaccine model to deliver antigens specifically to pDCs, we have demonstrated that pDC-targeted vaccination led to strong cross-priming and durable CD8 T cell immunity. Surprisingly, cross-presenting pDCs required conventional DCs (cDCs) to achieve cross-priming in vivo by transferring antigens to cDCs. Taking advantage of an in vitro system where only pDCs had access to antigens, we further demonstrated that cross-presenting pDCs were unable to efficiently prime CD8 T cells by themselves, but conferred antigen-naive cDCs the capability of cross-priming CD8 T cells by transferring antigens to cDCs. Although both cDC1s and cDC2s exhibited similar efficiency in acquiring antigens from pDCs, cDC1s but not cDC2s were required for cross-priming upon pDC-targeted vaccination, suggesting that cDC1s played a critical role in pDC-mediated cross-priming independent of their function in antigen presentation. Antigen transfer from pDCs to cDCs was mediated by previously unreported pDC-derived exosomes (pDCexos), that were also produced by pDCs under various conditions. Importantly, all these pDCexos primed naive antigen-specific CD8 T cells only in the presence of bystander cDCs, similarly to cross-presenting pDCs, thus identifying pDCexo-mediated antigen transfer to cDCs as a mechanism for pDCs to achieve cross-priming. In summary, our data suggest that pDCs employ a unique mechanism of pDCexo-mediated antigen transfer to cDCs for cross-priming.

scholarly journals Targeting of microRNA-142-3p in dendritic cells regulates endotoxin-induced mortality

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6172-6183 ◽  
Author(s):  
Yaping Sun ◽  
Sooryanarayana Varambally ◽  
Christopher A. Maher ◽  
Qi Cao ◽  
Peter Chockley ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Critical Role ◽  
Locked Nucleic Acid ◽  
Phosphorothioate Oligonucleotide ◽  
Unbiased Manner ◽  
Inflammatory Processes ◽  
Novel Strategy ◽  
Luciferase Reporters

Abstract While miRNAs are increasingly linked to various immune responses, whether they can be targeted for regulating in vivo inflammatory processes such as endotoxin-induced Gram-negative sepsis is not known. Production of cytokines by the dendritic cells (DCs) plays a critical role in response to endotoxin, lipopolysaccharide (LPS). We profiled the miRNA and mRNA of CD11c+ DCs in an unbiased manner and found that at baseline, miR-142-3p was among the most highly expressed endogenous miRs while IL-6 was among the most highly expressed mRNA after LPS stimulation. Multiple computational algorithms predicted the IL-6 3′ untranslated region (UTR) to be a target of miR-142-3p. Studies using luciferase reporters carrying wild-type (WT) and mutant IL-6 3′UTR confirmed IL-6 as a target for miR-142-3p. In vitro knockdown and overexpression studies demonstrated a critical and specific role for miR142-3p in regulating IL-6 production by the DCs after LPS stimulation. Importantly, treatment of only WT but not the IL-6–deficient (IL-6−/−) mice with locked nucleic acid (LNA)–modified phosphorothioate oligonucleotide complementary to miR 142-3p reduced endotoxin-induced mortality. These results demonstrate a critical role for miR-142-3p in regulating DC responses to LPS and provide proof of concept for targeting miRs as a novel strategy for treatment of endotoxin-induced mortality.

scholarly journals Effective Induction of Acquired Resistance to Listeria monocytogenes by Immunizing Mice with In Vivo-Infected Dendritic Cells

2003 ◽  
Vol 71 (1) ◽  
pp. 117-125 ◽  
Author(s):  
Hiroshi Sashinami ◽  
Akio Nakane ◽  
Yoichiro Iwakura ◽  
Mutsuo Sasaki
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Listeria Monocytogenes ◽  
Critical Role ◽  
Acquired Resistance ◽  
Interleukin 12 ◽  
Serovar Typhimurium ◽  
Ifn Γ

ABSTRACT Splenic dendritic cells (DCs) obtained from mice at 48 h after Listeria monocytogenes infection exhibited up-regulation of CD80 and produced higher titers of gamma interferon (IFN-γ) and interleukin-12 (IL-12) than did DCs obtained from uninfected mice. Mice immunized with DCs obtained from mice that had been infected with L. monocytogenes 48 h before acquired host resistance to lethal infection with L. monocytogenes at 4 and 8 weeks. Immunization with DCs from heat-killed L. monocytogenes failed to induce resistance. Acquired antilisterial resistance is specific, since the immunized mice could not be protected from Salmonella enterica serovar Typhimurium infection. Infected DCs stimulated proliferation of naive CD4+ and CD8+ cells in vitro, suggesting that in vivo-infected DCs activate CD8+ T cells, which are critical in acquired antilisterial resistance, as well as CD4+ T cells. When wild-type mice were immunized with DCs from IFN-γ-deficient mice, they were protected against a lethal L. monocytogenes challenge. In contrast, when mice were immunized with DCs from anti-IL-12 p40 monoclonal antibody-injected mice, they failed to gain acquired antilisterial resistance. These results suggest that DC-derived IL-12, but not IFN-γ, may play a critical role in induction of acquired antilisterial resistance. Our present results suggest that splenic DCs obtained from mice infected with L. monocytogenes in vivo may be an effective immunogen with which to induce antigen-specific immunity.

Poly I:C-based rHBVvac therapeutic vaccine eliminates HBV via generation of HBV-specific CD8+ effector memory T cells

Gut ◽  
2019 ◽  
Vol 68 (11) ◽  
pp. 2032-2043 ◽  
Author(s):  
Hua-Jun Zhao ◽  
Qiu-Ju Han ◽  
Guan Wang ◽  
Ang Lin ◽  
Dong-Qing Xu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Critical Role ◽  
Therapeutic Vaccine ◽  
Poly I:C ◽  
Effector Memory ◽  
Potential Candidate

ObjectiveChronic hepatitis B (CHB) virus infection is a global health problem. Finding a cure for CHB remains a challenging task.DesignIn this study, poly I:C was employed as an adjuvant for HBV therapeutic vaccine (referred to as pHBV-vaccine) and the feasibility and efficiency of pHBV-vaccine in CHB treatment were evaluated in HBV-carrier mice.ResultsWe found that pHBV-vaccine decreased HBsAg and HBV DNA efficiently and safely in HBV-carrier mice. Further investigation showed that pHBV-vaccine promoted maturation and antigen presentation ability of dendritic cells in vivo and in vitro. This vaccine successfully restored the exhaustion of antigen-specific CD8+ T cells and partly broke the immune tolerance established in HBV-carrier mice. pHBV-vaccine also enhanced the proliferation and polyfunctionality of HBV-specific CD11ahi CD8αlo cells. Importantly, we observed that T cell activation molecule KLRG1 was only expressed on HBV specific CD11ahi CD8αlo cells. Furthermore, pHBV-vaccine reduced the expression of Eomes and increased the serum IL-12 levels, which in turn promoted the generation of effector memory short-lived effector cells (SLECs) to exhibit a critical role in HBV clearance. SLECs induced by pHBV-vaccine might play a crucial role in protecting from HBV reinfection.ConclusionsFindings from this study provide a new basis for the development of therapeutic pHBV-vaccine, which might be a potential candidate for clinical CHB therapy.

scholarly journals Allogeneic dendritic cells induce potent antitumor immunity by activating KLRG1+CD8 T cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Chao Wang ◽  
Zhengyuan Li ◽  
Zhongli Zhu ◽  
Yijie Chai ◽  
Yiqing Wu ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd8 T Cells ◽  
Effector Memory ◽  
Functional Evaluation ◽  
Antigen Specificity ◽  
Tumor Vaccines ◽  
Efficient Protection

Abstract The graft-versus-leukemia effect reminds us to observe the allogeneic cell elicited anti-tumor immune responses. Here we immunized recipient B6 mice with different types of allogenic leukocytes and found that vaccination with allogenic dendritic cells (alloDC) elicited the most efficient protection against broad-spectrum tumors. The recipient lymphocytes were analyzed and the data showed that CD8 T cells increased significantly after immunization and expressed effector memory T cell marker KLRG1. Functional evaluation demonstrated that these KLRG1+CD8 T cells could kill tumor cells in vitro and in vivo in Granzyme B- and Fas/FasL-dependent manners with no tumor antigen specificity, and tend to migrate into tumor sites by high expression of heparanase. Adoptive transfer of these cells could provide antitumor protection against tumors. AlloDC could also treat mice with residual tumors and combination of anti-PD1 antibody could enhance this effects. Together, our study showed that alloDC-immunization could induce potent antitumor effect through the expansion of KLRG1+CD8 T cells, which can work as both preventive and therapeutic tumor vaccines.

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