The Experts below are selected from a list of 165 Experts worldwide ranked by ideXlab platform
Chyung-ru Wang - One of the best experts on this subject based on the ideXlab platform.
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Group 1 CD1-restricted T cells contribute to control of systemic Staphylococcus aureus infection.
PLoS pathogens, 2020Co-Authors: Lavanya Visvabharathy, Samantha Genardi, Liang Cao, Francis Alonzo, Evgeny Berdyshev, Chyung-ru WangAbstract:Staphylococcus aureus (SA) is the causative agent of both skin/soft tissue infections as well as invasive bloodstream infections. Though vaccines have been developed to target both humoral and T cell-mediated immune responses against SA, they have largely failed due to lack of protective efficacy. Group 1 CD1-restricted T cells recognize lipid rather than peptide antigens. Previously found to recognize lipids derived from cell wall of Mycobacterium tuberculosis (Mtb), these cells were associated with protection against Mtb infection in humans. Using a transgenic mouse model expressing human Group 1 CD1 molecules (hCD1Tg), we demonstrate that Group 1 CD1-restricted T cells can recognize SA-derived lipids in both immunization and infection settings. Systemic infection of hCD1Tg mice showed that SA-specific Group 1 CD1-restricted T cell response peaked at 10 days post-infection, and hCD1Tg mice displayed significantly decreased kidney pathology at this time point compared with WT control mice. Immunodominant SA lipid antigens recognized by Group 1 CD1-restricted T cells were comprised mainly of cardiolipin and phosphatidyl glycerol, with little contribution from lysyl-phosphatidyl glycerol which is a unique bacterial lipid not present in mammals. Group 1 CD1-restricted T cell lines specific for SA lipids also conferred protection against SA infection in the kidney after adoptive transfer. They were further able to effectively control SA replication in vitro through direct antigen presentation by Group 1 CD1-expressing BMDCs. Together, our data demonstrate a previously unknown role for Group 1 CD1-restricted SA lipid-specific T cells in the control of systemic MRSA infection.
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Linking CD1-Restricted T Cells With Autoimmunity and Dyslipidemia: Lipid Levels Matter.
Frontiers in immunology, 2018Co-Authors: Sreya Bagchi, Samantha Genardi, Chyung-ru WangAbstract:Dyslipidemia, or altered blood lipid content, is a risk factor for developing cardiovascular disease. Furthermore, several autoimmune diseases, including systemic lupus erythematosus, psoriasis, diabetes, and rheumatoid arthritis, are correlated highly with dyslipidemia. One common thread between both autoimmune diseases and altered lipid levels is the presence of inflammation, suggesting that the immune system might act as the link between these related pathologies. Deciphering the role of innate and adaptive immune responses in autoimmune diseases and, more recently, obesity-related inflammation, have been active areas of research. The broad picture suggests that antigen-presenting molecules, which present self-peptides to autoreactive T cells, can result in either aggravation or amelioration of inflammation. However, very little is known about the role of self-lipid reactive T cells in dyslipidemia-associated autoimmune events. Given that a range of autoimmune diseases are linked to aberrant lipid profiles and a majority of lipid-specific T cells are reactive to self-antigens, it is important to examine the role of these T cells in dyslipidemia-related autoimmune ailments and determine if dysregulation of these T cells can be drivers of autoimmune conditions. CD1 molecules present lipids to T cells and are divided into two Groups based on sequence homology. To date, most of the information available on lipid-reactive T cells comes from the study of Group 2 CD1d-restricted natural killer T (NKT) cells while T cells reactive to Group 1 CD1 molecules remain understudied, despite their higher abundance in humans compared to NKT cells. This review evaluates the mechanisms by which CD1-reactive, self-lipid specific T cells contribute to dyslipidemia-associated autoimmune disease progression or amelioration by examining available literature on NKT cells and highlighting recent progress made on the study of Group 1 CD1-restricted T cells.
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cd1b autoreactive t cells contribute to hyperlipidemia induced skin inflammation in mice
Journal of Clinical Investigation, 2017Co-Authors: Sreya Bagchi, Johann E Gudjonsson, Branch D Moody, Ildiko Van Rhijn, Ying He, Hong Zhang, Chyung-ru WangAbstract:: A large proportion of human T cells are autoreactive to Group 1 CD1 proteins, which include CD1a, CD1b, and CD1c. However, the physiological role of the CD1 proteins remains poorly defined. Here, we have generated a double-transgenic mouse model that expresses human CD1b and CD1c molecules (hCD1Tg) as well as a CD1b-autoreactive TCR (HJ1Tg) in the ApoE-deficient background (hCD1Tg HJ1Tg Apoe-/- mice) to determine the role of CD1-autoreactive T cells in hyperlipidemia-associated inflammatory diseases. We found that hCD1Tg HJ1Tg Apoe-/- mice spontaneously developed psoriasiform skin inflammation characterized by T cell and neutrophil infiltration and a Th17-biased cytokine response. Anti-IL-17A treatment ameliorated skin inflammation in vivo. Additionally, phospholipids and cholesterol preferentially accumulated in diseased skin and these autoantigens directly activated CD1b-autoreactive HJ1 T cells. Furthermore, hyperlipidemic serum enhanced IL-6 secretion by CD1b+ DCs and increased IL-17A production by HJ1 T cells. In psoriatic patients, the frequency of CD1b-autoreactive T cells was increased compared with that in healthy controls. Thus, this study has demonstrated the pathogenic role of CD1b-autoreactive T cells under hyperlipidemic conditions in a mouse model of spontaneous skin inflammation. As a large proportion of psoriatic patients are dyslipidemic, this finding is of clinical significance and indicates that self-lipid-reactive T cells might serve as a possible link between hyperlipidemia and psoriasis.
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CD1b-autoreactive T cells recognize phospholipid antigens and contribute to antitumor immunity against a CD1b+ T cell lymphoma
Oncoimmunology, 2016Co-Authors: Sreya Bagchi, Chyung-ru WangAbstract:Adoptive immunotherapy for cancer treatment is an emerging field of study. Till now, several tumor-derived, peptide-specific T cell responses have been harnessed for treating cancers. However, the contribution of lipid-specific T cells in tumor immunity has been understudied. CD1 molecules, which present self- and foreign lipid antigens to T cells, are divided into Group 1 (CD1a, CD1b, and CD1c) and Group 2 (CD1d). Although the role of CD1d-restricted natural killer T cells (NKT) in several tumor models has been well established, the contribution of Group 1 CD1-restricted T cells in tumor immunity remains obscure due to the lack of Group 1 CD1 expression in mice. In this study, we used a double transgenic mouse model expressing human Group 1 CD1 molecules (hCD1Tg) and a CD1b-restricted, self-lipid reactive T cell receptor (HJ1Tg) to study the potential role of Group 1 CD1-restricted autoreactive T cells in antitumor response. We found that HJ1 T cells recognized phospholipids and responded more potently to lipid extracted from tumor cells than the equivalent amount of lipids extracted from normal cells. Additionally, the autoreactivity of HJ1 T cells was enhanced upon treatment with various intracellular toll-like receptor (TLR) agonists, including CpG oligodeoxynucleotides (ODN), R848, and poly (I:C). Interestingly, the adoptive transfer of HJ1 T cells conferred protection against the CD1b-transfected murine T cell lymphoma (RMA-S/CD1b) and CpG ODN enhanced the antitumor effect. Thus, this study, for the first time, demonstrates the antitumor potential of CD1b-autoreactive T cells and their potential use in adoptive immunotherapy.
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Role of Group 1 CD1-Restricted T Cells in Infectious Disease.
Frontiers in immunology, 2015Co-Authors: Sarah Siddiqui, Lavanya Visvabharathy, Chyung-ru WangAbstract:The evolutionarily conserved CD1 family of antigen-presenting molecules presents lipid antigens rather than peptide antigens to T cells. CD1 molecules, unlike classical MHC molecules, display limited polymorphism, making CD1-restricted lipid antigens attractive vaccine targets that could be recognized in a genetically diverse human population. Group 1 CD1 (CD1a, CD1b, and CD1c)-restricted T cells have been implicated to play critical roles in a variety of autoimmune and infectious diseases. In this review, we summarize current knowledge and recent discoveries on the development of Group 1 CD1-restricted T cells and their function in different infection models. In particular, we focus on (1) newly identified microbial and self–lipid antigens, (2) kinetics, phenotype, and unique properties of Group 1 CD1-restricted T cells during infection, and (3) the similarities of Group 1 CD1-restricted T cells to the closely related Group 2 CD1-restricted T cells.
Masahiko Sugita - One of the best experts on this subject based on the ideXlab platform.
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Mycoketide: a CD1c-presented antigen with important implications in mycobacterial infection.
Clinical & developmental immunology, 2012Co-Authors: Isamu Matsunaga, Masahiko SugitaAbstract:Mycobacterium tuberculosis and related mycobacteria species are unique in that the acid-fast bacilli possess a highly lipid-rich cell wall that not simply confers resistance to treatment with acid alcohol, but also controls their survival and virulence. It has recently been established that a fraction of the cell wall lipid components of mycobacteria can function as antigens targeted by the acquired immunity of the host. Human Group 1 CD1 molecules (CD1a, CD1b, and CD1c) bind a pool of lipid antigens expressed by mycobacteria and present them to specific T cells, thereby mediating an effective pathway for host defense against tuberculosis. The contrasting and mutually complementary functions of CD1a and CD1b molecules in terms of the repertoire of antigens they bind have been well appreciated, but it remains to be established how CD1c may play a unique role. Nevertheless, recent advances in our understanding of the CD1c structure as well as the biosynthetic pathway of a CD1c-presented antigen, mannose-1, β-phosphomycoketide, expressed by pathogenic mycobacteria now unravel a new aspect of the Group 1 CD1 biology that has not been appreciated in previous studies of CD1a and CD1b molecules.
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Molecular and cellular biology of mycobacteria
Nihon rinsho. Japanese journal of clinical medicine, 2011Co-Authors: Yuki Hattori, Masahiko SugitaAbstract:The cell wall of mycobacteria contains mycobacteria-specific long-chain fatty acids, called mycolic acids, and mycolic acid-containing glycolipids. This highly hydrophobic structure of the cell wall of mycobacteria is critical not only for their acid-fast properties but also for their resistance to a variety of chemical attacks from the host cells, supporting their ability to survive for years within the host. On the other hand, the host T cells are capable of recognizing these critical lipid components of the cell wall of mycobacteria, such as glucose monomycolates, that are captured by Group 1 CD1 molecules. These T cells are able to eliminate mycobacteria-infected cells. This opens the possibility for a new type of lipid-based vaccines against tuberculosis.
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Trehalose Dimycolate Elicits Eosinophilic Skin Hypersensitivity in Mycobacteria-Infected Guinea Pigs
Journal of immunology (Baltimore Md. : 1950), 2008Co-Authors: Atsushi Otsuka, Isamu Matsunaga, Takaya Komori, Kadusa Tomita, Yoshinobu Toda, Toshiaki Manabe, Yoshiki Miyachi, Masahiko SugitaAbstract:Delayed-type hypersensitivity represents high levels of protein Ag-specific adaptive immunity induced by mycobacterial infection, and can be monitored in the Ag-challenged skin. Besides protein Ags, recent evidence has suggested that a substantial immunity directed against glycolipid Ags is also elicited in response to mycobacterial infection, but skin hypersensitivity to this class of Ags has not been fully assessed. To address this issue directly, glycolipid-specific skin reactions were evaluated in guinea pigs infected with Mycobacterium avium complex (MAC). Significant skin induration was observed in MAC-infected, but not mock-infected, guinea pigs, following intradermal administration of a mixture of MAC-derived glycolipids. Surprisingly, this glycolipid-specific skin response involved up-regulated expression of IL-5 mRNA in situ and marked local infiltration of eosinophils. Challenge experiments with individual glycolipid components detected an outstanding capability for trehalose dimycolate (TDM), but not a structurally related glycolipid, glucose monomycolate, to elicit the skin response. T lymphocytes derived from the spleen of MAC-infected, but not uninfected, guinea pigs specifically responded to TDM in vitro by up-regulating IL-5 transcription, and this response was not blocked by Abs that reacted to the known guinea pig Group 1 CD1 proteins. Finally, the eosinophilic skin hypersensitivity to TDM was also elicited in guinea pigs vaccinated with bacillus Calmette-Guerin, which contrasted sharply with the classical delayed-type hypersensitivity response to the purified protein derivative. Therefore, the TDM-elicited eosinophilic response defines a new form of hypersensitivity in mycobacterial infection, which may account for local infiltration of eosinophils often observed at the site of infection.
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Trans-species activation of human T cells by rhesus macaque CD1b molecules.
Biochemical and biophysical research communications, 2008Co-Authors: Daisuke Morita, Isamu Matsunaga, Kumiko Katoh, Toshiyuki Harada, Yoshiaki Nakagawa, Tomoyuki Miura, Akio Adachi, Tatsuhiko Igarashi, Masahiko SugitaAbstract:Despite crucial importance of non-human primates as a model of human infectious diseases, Group 1 CD1 genes and proteins have been poorly characterized in these species. Here, we isolated CD1A, CD1B, and CD1C cDNAs from rhesus macaque lymph nodes that encoded full-length CD1 proteins recognized specifically by monoclonal antibodies to human CD1a, CD1b, and CD1c molecules, respectively. The monkey Group 1 CD1 isoforms contained amino acid residues and motifs known to be critical for intramolecular disulfide bond formation, N-linked glycosylation, and endosomal trafficking as in human Group 1 CD1 molecules. Notably, monkey CD1b molecules were capable of presenting a mycobacterial glycolipid to human CD1b-restricted T cells, providing direct evidence for their antigen presentation function. This also detects for the first time a trans-species crossreaction mediated by Group 1 CD1 molecules. Taken together, these results underscore substantial conservation of the Group 1 CD1 system between humans and rhesus macaque monkeys.
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Cutting Edge: Guillain-Barré Syndrome-Associated IgG Responses to Gangliosides Are Generated Independently of CD1 Function in Mice
Journal of immunology (Baltimore Md. : 1950), 2007Co-Authors: Yukie Matsumoto, Nobuhiro Yuki, Luc Van Kaer, Koichi Furukawa, Koichi Hirata, Masahiko SugitaAbstract:CD1 molecules present a variety of microbial glycolipids and self-glycolipids to T cells, but their potential role in humoral responses to glycolipid Ags remains to be established. To address this issue directly, we used GM1/GD1a-deficient mice, which, upon immunization with heat-killed Campylobacter jejuni, develop Guillain-Barre syndrome-associated IgG Abs against the GM1/GD1a sugar chain epitopes of bacterial lipo-oligosaccharides (LOS). Our results showed that anti-ganglioside Abs of the IgG1, IgG2b, and IgG3 isotypes were produced in the absence of Group 2 CD1 (CD1d) expression. Unlike mouse and human Group 2 CD1 molecules that specifically bound LOS, none of the Group 1 CD1 molecules (CD1a, CD1b, and CD1c in humans) were capable of interacting with LOS. Thus, these results indicate CD1-independent pathways for anti-ganglioside Ab production.
Michael B. Brenner - One of the best experts on this subject based on the ideXlab platform.
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CD1-restricted adaptive immune responses to Mycobacteria in human Group 1 CD1 transgenic mice.
The Journal of experimental medicine, 2009Co-Authors: Kyrie Felio, Christopher C Dascher, Hanh Nguyen, Hak-jong Choi, Michael Zimmer, Angela Colmone, D. Branch Moody, Michael B. Brenner, Chyung-ru WangAbstract:Group 1 CD1 (CD1a, CD1b, and CD1c)–restricted T cells recognize mycobacterial lipid antigens and are found at higher frequencies in Mycobacterium tuberculosis (Mtb)–infected individuals. However, their role and dynamics during infection remain unknown because of the lack of a suitable small animal model. We have generated human Group 1 CD1 transgenic (hCD1Tg) mice that express all three human Group 1 CD1 isoforms and support the development of Group 1 CD1–restricted T cells with diverse T cell receptor usage. Both mycobacterial infection and immunization with Mtb lipids elicit Group 1 CD1–restricted Mtb lipid–specific T cell responses in hCD1Tg mice. In contrast to CD1d-restricted NKT cells, which rapidly respond to initial stimulation but exhibit anergy upon reexposure, Group 1 CD1–restricted T cells exhibit delayed primary responses and more rapid secondary responses, similar to conventional T cells. Collectively, our data demonstrate that Group 1 CD1–restricted T cells participate in adaptive immune responses upon mycobacterial infection and could serve as targets for the development of novel Mtb vaccines.
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Microsomal triglyceride transfer protein regulates endogenous and exogenous antigen presentation by Group 1 CD1 molecules.
European journal of immunology, 2008Co-Authors: Arthur Kaser, Michael B. Brenner, David L. Hava, Stephanie K. Dougan, Zhangguo Chen, Sebastian Zeissig, Richard S. BlumbergAbstract:Lipid antigens are presented to T cells by the non-polymorphic MHC class I-related CD1 molecules. Microsomal triglyceride transfer protein (MTP) is an endoplasmic reticulum (ER)-resident chaperone that has been shown to lipidate the Group 2 CD1 molecule CD1d and thus to regulate its function. We now report that MTP also regulates the function of Group 1 CD1 molecules CD1a, CD1b, and CD1c. Pharmacological inhibition of MTP in monocyte-derived dendritic cells and lymphoblastoid B cell lines transfected with Group 1 CD1 resulted in a substantial decrease in endogenous self lipid antigen presentation to several CD1-restricted T cell lines. Silencing MTP expression in CD1c-transfected HeLa cells similarly resulted in decreased self reactivity. Unexpectedly, inhibition of ER-resident MTP, which was confirmed by confocal microscopy, also markedly decreased presentation of exogenous, endosomally loaded, mycobacterial lipid antigens by CD1a and CD1c to T cells. Thus, these studies indicate that MTP, despite its ER localization, regulates endogenous as well as exogenous lipid antigen presentation, and suggest a broad role for MTP in the regulation of CD1 antigen presentation.
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Cutting Edge: Major CD8 T Cell Response to Live Bacillus Calmette-Guérin Is Mediated by CD1 Molecules
Journal of immunology (Baltimore Md. : 1950), 2003Co-Authors: Tetsuo Kawashima, Yoshihiko Norose, Yoshiyuki Watanabe, Yutaka Enomoto, Hidehiko Narazaki, Eiji Watari, Shigeo Tanaka, Hidemi Takahashi, Ikuya Yano, Michael B. BrennerAbstract:MHC class I-restricted CD8+ T cells are a crucial component of the host defense against mycobacterial infection in mice, but it has often proved very difficult to identify the CD8 T cell response in humans. Human Group 1 CD1 molecules (CD1a, -b, -c) mediate MHC-independent presentation of mycobacteria-derived lipid and glycolipid Ags to CD8+ T cells, and their intracellular localization to the endocytic system may favor efficient monitoring of phagosome-resident mycobacteria. Here, we show that bacillus Calmette-Guerin (BCG)-immunized subjects contain a significant circulating pool of CD8+ T cells that recognize BCG-infected DCs in a CD1-dependent, but MHC-independent, manner. These CD1-restricted T cells efficiently detected live, rather than dead, BCG and produced IFN-γ, an important cytokine for protection against mycobacterial infection. These results emphasize that lipid-reactive CD8+ T cells may contribute to host defense against mycobacterial infection.
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CD1 antigen presentation and infectious disease.
Contributions to microbiology, 2003Co-Authors: Christopher C Dascher, Michael B. BrennerAbstract:Abstract Taken together, the data generated thus far strongly suggest that CD1 plays a role in the immune response against various infections (table 1). For obvious reasons, the data gathered thus far using model infection systems have focused primarily on the mouse and therefore only examine the role of CD1d. This leaves an important gap in our understanding of the CD1 antigen presentation pathway given the potential role of CD1a, CD1b and CD1c for contributing to antimicrobial immunity. The functional dichotomy between Group 1 and Group 2 CD1 isoforms obviously requires further analysis. However, we propose that the Group 1 CD1 (CD1a, CD1b, CD1c) antigen presentation pathway is closer to the traditional adaptive immune response mechanisms with the capacity to present unique foreign antigens to specific T cells. This broadens the universe antigens that T cells can use to target pathogens and provides important antimicrobial effector mechanisms that may be critical for combating some types of infections. Lipid antigens may also provide a more effective means of targeting intracellular pathogens by T cells since CD1 is able to sample almost all of the intracellular reservoirs that are exploited by this class of pathogen and may provide an important component of the cytotoxic T cell response [80]. On the other hand, the Group 2 CD1 protein (CD1d) may be more intermediate in terms of lying functionally between the innate and adaptive immune systems. The activation of CD1d-restricted T cells may, therefore, help bridge the temporal gap between the onset of innate immunity and the purely adaptive responses typified by the MHC-restricted T cells. Hence, the CD1d-restricted [table: see text] T cells are primed for rapid high-level cytokine release. In addition, the interaction of CD1d-restricted T cells with CD1d on DCs can trigger the release of IL-4 and GM-CSF to promote maturation of tissue-resident DC at the site of infection. The maturation of tissue DC would lead to migration of the activated DC to regional lymph nodes and initiation of MHC-restricted T cell responses. Subsequent IL-12 production by the DC in response to CD1d-mediated T cell stimulation could then drive IFN-gamma production by CD1d-restricted T cells and influence the polarization of the T cell response to infection. In addition, early bursts of IFN-gamma by CD1d-restricted T cells could also upregulate antimicrobial activity in macrophages and activate other important effector cells such as NK cells prior to MHC-restricted T cell responses. In the constant struggle between the microbial pathogen and its host, the evolutionary balance almost always favors the microbe. The rapid rate of evolution and adaptation of the microbe accounts for most of this advantage. Hence, it is not surprising that the host immune system has evolved a complex set of pathways, in addition to the MHC, that are able to recognize and target the unique molecular signatures of infectious microorganisms. The lipid antigens presented by CD1 add to this array and thus provide a further layer of immune defense to the host for combating pathogens.
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Induction of CD1-Restricted Immune Responses in Guinea Pigs by Immunization with Mycobacterial Lipid Antigens
Journal of immunology (Baltimore Md. : 1950), 2002Co-Authors: Kenji Hiromatsu, Christopher C Dascher, Michael B. Brenner, Masahiko Sugita, Kenneth P. Leclair, Stephen T. Furlong, Steven A. PorcelliAbstract:Group 1 CD1 molecules have been shown to present lipid and glycolipid Ags of mycobacteria to human T cells. However, a suitable animal model for the investigation of this component of antimycobacterial immunity has not yet been established. Previously, we found that guinea pigs express multiple isoforms of Group 1 CD1 proteins that are homologous to human CD1b and CD1c. In this study, we show that CD1-restricted T cell responses can be generated in guinea pigs following immunization with lipid Ags from Mycobacterium tuberculosis. Splenic T cells from lipid Ag-immunized guinea pigs showed strong proliferative responses to total lipid Ags and partially purified glycolipid fractions from M. tuberculosis. These lipid Ag-reactive T cells were enriched in CD4-negative T cell fractions and showed cytotoxic activity against CD1-expressing guinea pig bone marrow-derived dendritic cells pulsed with M. tuberculosis lipid Ags. Using guinea pig cell lines transfected with individual CD1 isoforms as target cells in cytotoxic T cell assays, we found that guinea pig CD1b and CD1c molecules presented M. tuberculosis glycolipid Ags to T cells raised by mycobacterial lipid immunization. These results were confirmed using a T cell line derived from M. tuberculosis lipid Ag-immunized guinea pigs, which also showed CD1-restricted responses and cytolytic activity. Our results demonstrate that CD1-restricted responses against microbial glycolipid Ags can be generated in vivo by specific immunization and provide support for the use of the guinea pig as a relevant small animal model for the study of CD1-restricted immune responses to mycobacterial pathogens.
Sreya Bagchi - One of the best experts on this subject based on the ideXlab platform.
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Linking CD1-Restricted T Cells With Autoimmunity and Dyslipidemia: Lipid Levels Matter.
Frontiers in immunology, 2018Co-Authors: Sreya Bagchi, Samantha Genardi, Chyung-ru WangAbstract:Dyslipidemia, or altered blood lipid content, is a risk factor for developing cardiovascular disease. Furthermore, several autoimmune diseases, including systemic lupus erythematosus, psoriasis, diabetes, and rheumatoid arthritis, are correlated highly with dyslipidemia. One common thread between both autoimmune diseases and altered lipid levels is the presence of inflammation, suggesting that the immune system might act as the link between these related pathologies. Deciphering the role of innate and adaptive immune responses in autoimmune diseases and, more recently, obesity-related inflammation, have been active areas of research. The broad picture suggests that antigen-presenting molecules, which present self-peptides to autoreactive T cells, can result in either aggravation or amelioration of inflammation. However, very little is known about the role of self-lipid reactive T cells in dyslipidemia-associated autoimmune events. Given that a range of autoimmune diseases are linked to aberrant lipid profiles and a majority of lipid-specific T cells are reactive to self-antigens, it is important to examine the role of these T cells in dyslipidemia-related autoimmune ailments and determine if dysregulation of these T cells can be drivers of autoimmune conditions. CD1 molecules present lipids to T cells and are divided into two Groups based on sequence homology. To date, most of the information available on lipid-reactive T cells comes from the study of Group 2 CD1d-restricted natural killer T (NKT) cells while T cells reactive to Group 1 CD1 molecules remain understudied, despite their higher abundance in humans compared to NKT cells. This review evaluates the mechanisms by which CD1-reactive, self-lipid specific T cells contribute to dyslipidemia-associated autoimmune disease progression or amelioration by examining available literature on NKT cells and highlighting recent progress made on the study of Group 1 CD1-restricted T cells.
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cd1b autoreactive t cells contribute to hyperlipidemia induced skin inflammation in mice
Journal of Clinical Investigation, 2017Co-Authors: Sreya Bagchi, Johann E Gudjonsson, Branch D Moody, Ildiko Van Rhijn, Ying He, Hong Zhang, Chyung-ru WangAbstract:: A large proportion of human T cells are autoreactive to Group 1 CD1 proteins, which include CD1a, CD1b, and CD1c. However, the physiological role of the CD1 proteins remains poorly defined. Here, we have generated a double-transgenic mouse model that expresses human CD1b and CD1c molecules (hCD1Tg) as well as a CD1b-autoreactive TCR (HJ1Tg) in the ApoE-deficient background (hCD1Tg HJ1Tg Apoe-/- mice) to determine the role of CD1-autoreactive T cells in hyperlipidemia-associated inflammatory diseases. We found that hCD1Tg HJ1Tg Apoe-/- mice spontaneously developed psoriasiform skin inflammation characterized by T cell and neutrophil infiltration and a Th17-biased cytokine response. Anti-IL-17A treatment ameliorated skin inflammation in vivo. Additionally, phospholipids and cholesterol preferentially accumulated in diseased skin and these autoantigens directly activated CD1b-autoreactive HJ1 T cells. Furthermore, hyperlipidemic serum enhanced IL-6 secretion by CD1b+ DCs and increased IL-17A production by HJ1 T cells. In psoriatic patients, the frequency of CD1b-autoreactive T cells was increased compared with that in healthy controls. Thus, this study has demonstrated the pathogenic role of CD1b-autoreactive T cells under hyperlipidemic conditions in a mouse model of spontaneous skin inflammation. As a large proportion of psoriatic patients are dyslipidemic, this finding is of clinical significance and indicates that self-lipid-reactive T cells might serve as a possible link between hyperlipidemia and psoriasis.
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CD1b-autoreactive T cells recognize phospholipid antigens and contribute to antitumor immunity against a CD1b+ T cell lymphoma
Oncoimmunology, 2016Co-Authors: Sreya Bagchi, Chyung-ru WangAbstract:Adoptive immunotherapy for cancer treatment is an emerging field of study. Till now, several tumor-derived, peptide-specific T cell responses have been harnessed for treating cancers. However, the contribution of lipid-specific T cells in tumor immunity has been understudied. CD1 molecules, which present self- and foreign lipid antigens to T cells, are divided into Group 1 (CD1a, CD1b, and CD1c) and Group 2 (CD1d). Although the role of CD1d-restricted natural killer T cells (NKT) in several tumor models has been well established, the contribution of Group 1 CD1-restricted T cells in tumor immunity remains obscure due to the lack of Group 1 CD1 expression in mice. In this study, we used a double transgenic mouse model expressing human Group 1 CD1 molecules (hCD1Tg) and a CD1b-restricted, self-lipid reactive T cell receptor (HJ1Tg) to study the potential role of Group 1 CD1-restricted autoreactive T cells in antitumor response. We found that HJ1 T cells recognized phospholipids and responded more potently to lipid extracted from tumor cells than the equivalent amount of lipids extracted from normal cells. Additionally, the autoreactivity of HJ1 T cells was enhanced upon treatment with various intracellular toll-like receptor (TLR) agonists, including CpG oligodeoxynucleotides (ODN), R848, and poly (I:C). Interestingly, the adoptive transfer of HJ1 T cells conferred protection against the CD1b-transfected murine T cell lymphoma (RMA-S/CD1b) and CpG ODN enhanced the antitumor effect. Thus, this study, for the first time, demonstrates the antitumor potential of CD1b-autoreactive T cells and their potential use in adoptive immunotherapy.
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Self-lipid specific T cells, restricted by CD1b, contribute to the development of hyperlipidemia-associated skin inflammation (BA11P.133)
Journal of Immunology, 2015Co-Authors: Sreya Bagchi, Hong Zhang, Chyung-ru WangAbstract:Psoriasis, a chronic inflammatory skin disease, is associated with hyperlipidemia. While conventional T cells usually exacerbate psoriasis, the role of self-lipid reactive CD1-restricted T cells requires further study. CD1 molecules present lipid antigens to T cells and are divided in to two Groups. Group 1 includes CD1a, CD1b, CD1c while CD1d belongs to Group 2. Humans express both Group 1 and Group 2 CD1 molecules whereas mice only have CD1d. Thus, due to the lack of a suitable animal model, the role of autoreactive Group 1 CD1-restricted T cells in hyperlipidemia-associated inflammatory diseases is unknown. To overcome this challenge, our lab generated mice that expressed human CD1b and a CD1b-autoreactive T cell receptor (hCD1Tg/HJ1Tg). hCD1Tg/HJ1Tg mice were crossed to the ApoE-/- background to examine the role of CD1b-restricted T cells in hyperlipidemia (hCD1Tg/HJ1Tg/ApoE-/-). Interestingly, hCD1Tg/HJ1Tg/ApoE-/- mice developed severe psoriasis-like skin inflammation characterized by T cell and neutrophil infiltration along with a Th17-biased cytokine milieu. They also showed significantly increased polar lipid accumulation in the skin as compared to hCD1Tg/HJ1Tg/ApoE+ mice. This suggested that the presence of excessive lipids in the skin resulted in activation of CD1b-autoreacitve T cells, leading to the onset of skin pathology. This work demonstrates that autoreactive Group 1 CD1-reactive T cells might serve as a link between inflammatory processes and hyperlipidemia.
Steven A. Porcelli - One of the best experts on this subject based on the ideXlab platform.
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CD1-restricted T cells in host defense to infectious diseases.
Current topics in microbiology and immunology, 2007Co-Authors: Samuel M. Behar, Steven A. PorcelliAbstract:CD1 has been clearly shown to function as a microbial recognition system for activation of T cell responses, but its importance for mammalian protective responses against infections is still uncertain. The function of the Group 1 CD1 isoforms, including human CD1a, CDlb, and CDLc, seems closely linked to adaptive immunity. These CD1 molecules control the responses of T cells that are highly specific for particular lipid antigens, the best known of which are abundantly expressed by pathogenic mycobacteria such as Mycobacterium tuberculosis and Mycobacterium leprae. Studies done mainly on human circulating T cells ex vivo support a significant role for Group I CD1-restricted T cells in protective immunity to mycobacteria and potentially other pathogens, although supportive data from animal models is currently limited. In contrast, Group 2 CD1 molecules, which include human CD1d and its orthologs, have been predominantly associated with the activation of CD1d-restricted NKT cells, which appear to be more appropriately viewed as a facet of the innate immune system. Whereas the recognition of certain self-lipid ligands by CD d-restricted NKT cells is well accepted, the importance of these T cells in mediating adaptive immune recognition of specific microbial lipid antigens remains controversial. Despite continuing uncertainty about the role of CD 1d-restricted NKT cells in natural infections, studies in mouse models demonstrate the potential of these T cells to exert various effects on a wide spectrum of infectious diseases, most likely by serving as a bridge between innate and adaptive immune responses.
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Upregulation of Group 1 CD1 antigen presenting molecules in guinea pigs with experimental autoimmune encephalomyelitis: An immunohistochemical study
Brain pathology (Zurich Switzerland), 2006Co-Authors: Barbara Cipriani, Kenji Hiromatsu, Steven A. Porcelli, Lanfen Chen, Heather Knowles, Cedric S. Raine, Luca Battistini, Celia F. BrosnanAbstract:In humans, Group 1 CD1 glycoproteins present foreign and self lipid and glycolipid antigens to T-cells. Homologues of these molecules are not found in mice or rats but are present in guinea pigs (GPs). We examined CD1 and MHC class II expression in the central nervous system (CNS) of GPs sensitized for experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. In normal GPs and the uninflamed CNS, low-level MHC class II (MHC II) immunoreactivity occurred on vascular elements, meningeal macrophages and parenchymal microglial cells, whereas immunoreactivity for CD1 was absent. In the inflamed CNS, the majority of infiltrating cells were MHC II+ and microglia showed increased expression. CD1 immunoreactivity was detected on astrocytes and subsets of inflammatory cells Including B cells and macrophages. Minimal CD1 and MHC II co-expression was noted on inflammatory cells or glia. We conclude that Group 1 CD1 molecules are strongly upregulated in the inflamed CNS on subsets of cells distinct from the majority of MHC II bearing cells. The expression of CD1 proteins in such lesions broadens the potential repertoire of antigens recognized at these sites and highlights the value of the GP as a model for studies of the relevance of CD1 molecules in host defense and autoimmune diseases.
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The Bovine CD1 Family Contains Group 1 CD1 Proteins, but No Functional CD1d
Journal of immunology (Baltimore Md. : 1950), 2006Co-Authors: Ildiko Van Rhijn, Steven A. Porcelli, Ad P. Koets, Diewertje Piebes, Faye Reddington, Gurdyal S. Besra, Willem Van Eden, Victor P.m.g. RuttenAbstract:The CD1 family of proteins presents lipid Ags to T cells. Human CD1a, CD1b, and CD1c have been shown in humans to present mycobacterial lipid Ags. Cattle, like humans, are a natural host of several mycobacterial pathogens. In this study, we describe the CD1 family of genes in cattle (Bos taurus) and provide evidence that B. taurus expresses CD1a, CD1e, and multiple CD1b molecules, but no CD1c and CD1d molecules. In mice and humans, CD1d is known to present Ag to NKT cells, a T cell lineage that is characterized by a limited TCR repertoire, capable of rapidly secreting large amounts of IFN-γ and IL-4. In cattle, two CD1D pseudogenes were found and no intact CD1D genes. Consistent with this, we found complete lack of reactivity to a potent, cross-reactive Ag for NKT cells in mice and humans, α-galactosylceramide. Our data suggest the absence of NKT cells in cattle. It remains open whether other cells with the NKT-like phenotype and functions are present in this species. With its functional CD1A and CD1B genes, B. taurus is well equipped to present Ags to CD1-restricted T cells other than NKT cells. Cattle can be used as a model to study Group 1 CD1-restricted T cell immunity, including its role in the defense against mycobacterial infections that occur naturally in this species.
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Direct Measurement of Antigen Binding Properties of CD1 Proteins Using Fluorescent Lipid Probes
The Journal of biological chemistry, 2003Co-Authors: Petr A. Illarionov, Kenneth P. Leclair, Gurdyal S. Besra, James R. Storey, Malcolm W. Kennedy, Steven A. PorcelliAbstract:CD1 proteins are antigen-presenting molecules that bind foreign and self-lipids and stimulate specific T cell responses. In the current study, we investigated ligand binding by CD1 proteins by developing a fluorescent probe binding approach using soluble recombinant human CD1 proteins. To increase stability and yield, soluble Group 1 CD1 (CD1b and CD1c) and Group 2 CD1 (CD1d) proteins were produced as single chain secreted CD1 proteins in which beta2-microglobulin was fused to the N termini of the CD1 heavy chains by a flexible peptide linker sequence. Analysis of ligand binding properties of single chain secreted CD1 proteins by using fluorescent lipid probes indicated significant differences in ligand preference and in pH dependence of binding by Group 1 versus Group 2 CD1 proteins. Whereas Group 1 CD1 isoforms (CD1b and CD1c) show stronger binding of nitrobenzoxadiazole (NBD)-labeled dialkyl-based ligands (phosphatidylcholine, sphingomyelin, and ceramide), Group 2 CD1 (CD1d) proteins were stronger binders of small hydrophobic probes such as 1-anilinonaphthalene-8-sulfonic acid and 4,4'-dianilino-1,1'-naphthyl-5,5'-disulfonic acid. Competition studies indicated that binding of fluorescent lipid probes involved association of the probe with the hydrophobic ligand binding groove of CD1 proteins. Analysis of selected alanine substitution mutants of human CD1b known to inhibit antigen presentation showed that NBD-labeled lipid probe binding could be used to distinguish mutations that interfere with ligand binding from those that affect T cell receptor docking. Our findings provide further evidence for the functional specialization of different CD1 isoforms and demonstrate the value of the fluorescent lipid probe binding method for assisting structure-based studies of CD1 function.
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Induction of CD1-Restricted Immune Responses in Guinea Pigs by Immunization with Mycobacterial Lipid Antigens
Journal of immunology (Baltimore Md. : 1950), 2002Co-Authors: Kenji Hiromatsu, Christopher C Dascher, Michael B. Brenner, Masahiko Sugita, Kenneth P. Leclair, Stephen T. Furlong, Steven A. PorcelliAbstract:Group 1 CD1 molecules have been shown to present lipid and glycolipid Ags of mycobacteria to human T cells. However, a suitable animal model for the investigation of this component of antimycobacterial immunity has not yet been established. Previously, we found that guinea pigs express multiple isoforms of Group 1 CD1 proteins that are homologous to human CD1b and CD1c. In this study, we show that CD1-restricted T cell responses can be generated in guinea pigs following immunization with lipid Ags from Mycobacterium tuberculosis. Splenic T cells from lipid Ag-immunized guinea pigs showed strong proliferative responses to total lipid Ags and partially purified glycolipid fractions from M. tuberculosis. These lipid Ag-reactive T cells were enriched in CD4-negative T cell fractions and showed cytotoxic activity against CD1-expressing guinea pig bone marrow-derived dendritic cells pulsed with M. tuberculosis lipid Ags. Using guinea pig cell lines transfected with individual CD1 isoforms as target cells in cytotoxic T cell assays, we found that guinea pig CD1b and CD1c molecules presented M. tuberculosis glycolipid Ags to T cells raised by mycobacterial lipid immunization. These results were confirmed using a T cell line derived from M. tuberculosis lipid Ag-immunized guinea pigs, which also showed CD1-restricted responses and cytolytic activity. Our results demonstrate that CD1-restricted responses against microbial glycolipid Ags can be generated in vivo by specific immunization and provide support for the use of the guinea pig as a relevant small animal model for the study of CD1-restricted immune responses to mycobacterial pathogens.
