Tumor-derived alpha-fetoprotein impairs the differentiation and T cell stimulatory activity of human dendritic cells
Identifieur interne : 000A58 ( Main/Exploration ); précédent : 000A57; suivant : 000A59Tumor-derived alpha-fetoprotein impairs the differentiation and T cell stimulatory activity of human dendritic cells
Auteurs : Angela D. Pardee [États-Unis] ; Jian Shi [États-Unis] ; Lisa H. Butterfield [États-Unis]Source :
- Journal of immunology (Baltimore, Md. : 1950) [ 0022-1767 ] ; 2014.
Descripteurs français
- KwdFr :
- Activation des lymphocytes, Alphafoetoprotéines (immunologie), Alphafoetoprotéines (métabolisme), Antigènes CD (métabolisme), Carcinome hépatocellulaire (métabolisme), Cellules HepG2, Cellules dendritiques (immunologie), Chaperons moléculaires (immunologie), Chaperons moléculaires (métabolisme), Cytokines (métabolisme), Différenciation cellulaire, Humains, Immunophénotypage, Lymphocytes T (immunologie), Médiateurs de l'inflammation (métabolisme), Prolifération cellulaire, Sang foetal (métabolisme).
- MESH :
- immunologie : Alphafoetoprotéines, Cellules dendritiques, Chaperons moléculaires, Lymphocytes T.
- métabolisme : Alphafoetoprotéines, Antigènes CD, Carcinome hépatocellulaire, Chaperons moléculaires, Cytokines, Médiateurs de l'inflammation, Sang foetal.
- Activation des lymphocytes, Cellules HepG2, Différenciation cellulaire, Humains, Immunophénotypage, Prolifération cellulaire.
English descriptors
- KwdEn :
- Antigens, CD (metabolism), Carcinoma, Hepatocellular (metabolism), Cell Differentiation, Cell Proliferation, Cytokines (metabolism), Dendritic Cells (immunology), Fetal Blood (metabolism), Hep G2 Cells, Humans, Immunophenotyping, Inflammation Mediators (metabolism), Lymphocyte Activation, Molecular Chaperones (immunology), Molecular Chaperones (metabolism), T-Lymphocytes (immunology), alpha-Fetoproteins (immunology), alpha-Fetoproteins (metabolism).
- MESH :
- chemical , immunology : Molecular Chaperones, alpha-Fetoproteins.
- chemical , metabolism : Antigens, CD, Cytokines, Inflammation Mediators, Molecular Chaperones, alpha-Fetoproteins.
- immunology : Dendritic Cells, T-Lymphocytes.
- metabolism : Carcinoma, Hepatocellular, Fetal Blood.
- Cell Differentiation, Cell Proliferation, Hep G2 Cells, Humans, Immunophenotyping, Lymphocyte Activation.
Abstract
Several tumor-derived factors have been implicated in DC dysfunction in cancer patients. Alpha-fetoprotein (AFP) is an oncofetal antigen that is highly expressed in abnormalities of prenatal development and several epithelial cancers, including hepatocellular carcinoma (HCC). In HCC patients exhibiting high levels of serum AFP, we have observed a lower ratio of myeloid-to-plasmacytoid circulating DC compared to patients with low serum AFP levels and healthy donors. To test the effect of AFP on DC differentiation in vitro, peripheral blood monocytes from healthy donors were cultured in the presence of cord blood-derived normal AFP (nAFP) or HCC tumor-derived AFP (tAFP), and DC phenotype and function was assessed. Although the nAFP and tAFP isoforms only differ at one carbohydrate group, low (physiological) levels of tAFP, but not nAFP, significantly inhibited DC differentiation. tAFP-conditioned DC expressed diminished levels of DC maturation markers, retained a monocyte-like morphology, exhibited limited production of inflammatory mediators, and failed to induce robust T cell proliferative responses. Mechanistic studies revealed that the suppressive activity of tAFP is dependent on the presence of low molecular weight (LMW) species that
Url:
DOI: 10.4049/jimmunol.1400725
PubMed: 25355916
PubMed Central: 4239186
Affiliations:
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Le document en format XML
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Pardee</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Shi, Jian" sort="Shi, Jian" uniqKey="Shi J" first="Jian" last="Shi">Jian Shi</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Butterfield, Lisa H" sort="Butterfield, Lisa H" uniqKey="Butterfield L" first="Lisa H." last="Butterfield">Lisa H. Butterfield</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="A2">Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="A3">Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="A4">University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>University of Pittsburgh Cancer Institute, Pittsburgh</wicri:cityArea></affiliation></author></analytic><series><title level="j">Journal of immunology (Baltimore, Md. : 1950)</title><idno type="ISSN">0022-1767</idno><idno type="eISSN">1550-6606</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antigens, CD (metabolism)</term><term>Carcinoma, Hepatocellular (metabolism)</term><term>Cell Differentiation</term><term>Cell Proliferation</term><term>Cytokines (metabolism)</term><term>Dendritic Cells (immunology)</term><term>Fetal Blood (metabolism)</term><term>Hep G2 Cells</term><term>Humans</term><term>Immunophenotyping</term><term>Inflammation Mediators (metabolism)</term><term>Lymphocyte Activation</term><term>Molecular Chaperones (immunology)</term><term>Molecular Chaperones (metabolism)</term><term>T-Lymphocytes (immunology)</term><term>alpha-Fetoproteins (immunology)</term><term>alpha-Fetoproteins (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Activation des lymphocytes</term><term>Alphafoetoprotéines (immunologie)</term><term>Alphafoetoprotéines (métabolisme)</term><term>Antigènes CD (métabolisme)</term><term>Carcinome hépatocellulaire (métabolisme)</term><term>Cellules HepG2</term><term>Cellules dendritiques (immunologie)</term><term>Chaperons moléculaires (immunologie)</term><term>Chaperons moléculaires (métabolisme)</term><term>Cytokines (métabolisme)</term><term>Différenciation cellulaire</term><term>Humains</term><term>Immunophénotypage</term><term>Lymphocytes T (immunologie)</term><term>Médiateurs de l'inflammation (métabolisme)</term><term>Prolifération cellulaire</term><term>Sang foetal (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Molecular Chaperones</term><term>alpha-Fetoproteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antigens, CD</term><term>Cytokines</term><term>Inflammation Mediators</term><term>Molecular Chaperones</term><term>alpha-Fetoproteins</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Alphafoetoprotéines</term><term>Cellules dendritiques</term><term>Chaperons moléculaires</term><term>Lymphocytes T</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Dendritic Cells</term><term>T-Lymphocytes</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Carcinoma, Hepatocellular</term><term>Fetal Blood</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Alphafoetoprotéines</term><term>Antigènes CD</term><term>Carcinome hépatocellulaire</term><term>Chaperons moléculaires</term><term>Cytokines</term><term>Médiateurs de l'inflammation</term><term>Sang foetal</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Differentiation</term><term>Cell Proliferation</term><term>Hep G2 Cells</term><term>Humans</term><term>Immunophenotyping</term><term>Lymphocyte Activation</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Activation des lymphocytes</term><term>Cellules HepG2</term><term>Différenciation cellulaire</term><term>Humains</term><term>Immunophénotypage</term><term>Prolifération cellulaire</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">Several tumor-derived factors have been implicated in DC dysfunction in cancer patients. Alpha-fetoprotein (AFP) is an oncofetal antigen that is highly expressed in abnormalities of prenatal development and several epithelial cancers, including hepatocellular carcinoma (HCC). In HCC patients exhibiting high levels of serum AFP, we have observed a lower ratio of myeloid-to-plasmacytoid circulating DC compared to patients with low serum AFP levels and healthy donors. To test the effect of AFP on DC differentiation in vitro, peripheral blood monocytes from healthy donors were cultured in the presence of cord blood-derived normal AFP (nAFP) or HCC tumor-derived AFP (tAFP), and DC phenotype and function was assessed. Although the nAFP and tAFP isoforms only differ at one carbohydrate group, low (physiological) levels of tAFP, but not nAFP, significantly inhibited DC differentiation. tAFP-conditioned DC expressed diminished levels of DC maturation markers, retained a monocyte-like morphology, exhibited limited production of inflammatory mediators, and failed to induce robust T cell proliferative responses. Mechanistic studies revealed that the suppressive activity of tAFP is dependent on the presence of low molecular weight (LMW) species that <italic>i</italic>) co-purify with tAFP, and <italic>ii</italic>) function equivalently to the LMW fractions of both tumor and non-tumor cell lysates. These data reveal the unique ability of tAFP to serve as a chaperone protein for LMW molecules, both endogenous and ubiquitous in nature, which function cooperatively to impair DC differentiation and function. Therefore, novel therapeutic approaches that antagonize the regulatory properties of tAFP will be critical to enhance immunity and improve clinical outcomes.</p></div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Pennsylvanie</li></region></list><tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Pardee, Angela D" sort="Pardee, Angela D" uniqKey="Pardee A" first="Angela D." last="Pardee">Angela D. Pardee</name></region><name sortKey="Butterfield, Lisa H" sort="Butterfield, Lisa H" uniqKey="Butterfield L" first="Lisa H." last="Butterfield">Lisa H. Butterfield</name><name sortKey="Butterfield, Lisa H" sort="Butterfield, Lisa H" uniqKey="Butterfield L" first="Lisa H." last="Butterfield">Lisa H. Butterfield</name><name sortKey="Butterfield, Lisa H" sort="Butterfield, Lisa H" uniqKey="Butterfield L" first="Lisa H." last="Butterfield">Lisa H. Butterfield</name><name sortKey="Butterfield, Lisa H" sort="Butterfield, Lisa H" uniqKey="Butterfield L" first="Lisa H." last="Butterfield">Lisa H. Butterfield</name><name sortKey="Shi, Jian" sort="Shi, Jian" uniqKey="Shi J" first="Jian" last="Shi">Jian Shi</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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