Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease
Identifieur interne : 000942 ( Ncbi/Checkpoint ); précédent : 000941; suivant : 000943Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease
Auteurs : Vanessa Brochard [France] ; Béhazine Combadière [France] ; Annick Prigent [France] ; Yasmina Laouar [États-Unis] ; Aline Perrin [France] ; Virginie Beray-Berthat [France] ; Olivia Bonduelle [France] ; Daniel Alvarez-Fischer [France] ; Jacques Callebert [France] ; Jean-Marie Launay [France] ; Charles Duyckaerts [France] ; Richard A. Flavell [États-Unis] ; Etienne C. Hirsch [France] ; Stéphane Hunot [France]Source :
- The Journal of Clinical Investigation [ 0021-9738 ] ; 2008.
English descriptors
- KwdEn :
- Aged, Aged, 80 and over, Animals, Brain (cytology), Brain (immunology), Brain (pathology), CD4-Positive T-Lymphocytes (cytology), CD4-Positive T-Lymphocytes (immunology), Cell Death (physiology), Disease Models, Animal, Dopamine (metabolism), Fas Ligand Protein (genetics), Fas Ligand Protein (metabolism), Homeodomain Proteins (genetics), Homeodomain Proteins (metabolism), Humans, Immune System (physiology), Interferon-gamma (metabolism), Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Degeneration (immunology), Nerve Degeneration (pathology), Neurons (cytology), Neurons (metabolism), Neurons (pathology), Parkinson Disease (immunology), Parkinson Disease (pathology), Parkinsonian Disorders (immunology), Parkinsonian Disorders (pathology).
- MESH :
- chemical , genetics : Fas Ligand Protein, Homeodomain Proteins.
- chemical , metabolism : Dopamine, Fas Ligand Protein, Homeodomain Proteins, Interferon-gamma.
- cytology : Brain, CD4-Positive T-Lymphocytes, Neurons.
- immunology : Brain, CD4-Positive T-Lymphocytes, Nerve Degeneration, Parkinson Disease, Parkinsonian Disorders.
- metabolism : Neurons.
- pathology : Brain, Nerve Degeneration, Neurons, Parkinson Disease, Parkinsonian Disorders.
- physiology : Cell Death, Immune System.
- Aged, Aged, 80 and over, Animals, Disease Models, Animal, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout.
Abstract
Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of dopamine-containing neurons. Mounting evidence suggests that dopaminergic cell death is influenced by the innate immune system. However, the pathogenic role of the adaptive immune system in PD remains enigmatic. Here we showed that CD8+ and CD4+ T cells but not B cells had invaded the brain in both postmortem human PD specimens and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD during the course of neuronal degeneration. We further demonstrated that MPTP-induced dopaminergic cell death was markedly attenuated in the absence of mature T lymphocytes in 2 different immunodeficient mouse strains (
Url:
DOI: 10.1172/JCI36470
PubMed: 19104149
PubMed Central: 2613467
Affiliations:
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PMC:2613467Le document en format XML
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<affiliation wicri:level="3"><nlm:aff id="JCI36470">Université Pierre et Marie Curie — Paris 06, UMR S679, Paris, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Université Pierre et Marie Curie — Paris 06, UMR S679, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Beray Berthat, Virginie" sort="Beray Berthat, Virginie" uniqKey="Beray Berthat V" first="Virginie" last="Beray-Berthat">Virginie Beray-Berthat</name>
<affiliation wicri:level="3"><nlm:aff id="JCI36470">INSERM, UMR S679, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, Paris, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>INSERM, UMR S679, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI36470">Université Pierre et Marie Curie — Paris 06, UMR S679, Paris, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Université Pierre et Marie Curie — Paris 06, UMR S679, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bonduelle, Olivia" sort="Bonduelle, Olivia" uniqKey="Bonduelle O" first="Olivia" last="Bonduelle">Olivia Bonduelle</name>
<affiliation wicri:level="3"><nlm:aff id="JCI36470">INSERM U543, Université Pierre et Marie Curie — Paris 06, Paris, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>INSERM U543, Université Pierre et Marie Curie — Paris 06, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Alvarez Fischer, Daniel" sort="Alvarez Fischer, Daniel" uniqKey="Alvarez Fischer D" first="Daniel" last="Alvarez-Fischer">Daniel Alvarez-Fischer</name>
<affiliation wicri:level="3"><nlm:aff id="JCI36470">INSERM, UMR S679, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, Paris, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>INSERM, UMR S679, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI36470">Université Pierre et Marie Curie — Paris 06, UMR S679, Paris, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Université Pierre et Marie Curie — Paris 06, UMR S679, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Callebert, Jacques" sort="Callebert, Jacques" uniqKey="Callebert J" first="Jacques" last="Callebert">Jacques Callebert</name>
<affiliation wicri:level="3"><nlm:aff id="JCI36470">CR Claude Bernard, IFR6, Service de Biochimie, Hôpital Lariboisière, Assistance Publique — Hôpitaux de Paris, Paris, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>CR Claude Bernard, IFR6, Service de Biochimie, Hôpital Lariboisière, Assistance Publique — Hôpitaux de Paris, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Launay, Jean Marie" sort="Launay, Jean Marie" uniqKey="Launay J" first="Jean-Marie" last="Launay">Jean-Marie Launay</name>
<affiliation wicri:level="3"><nlm:aff id="JCI36470">CR Claude Bernard, IFR6, Service de Biochimie, Hôpital Lariboisière, Assistance Publique — Hôpitaux de Paris, Paris, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>CR Claude Bernard, IFR6, Service de Biochimie, Hôpital Lariboisière, Assistance Publique — Hôpitaux de Paris, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Duyckaerts, Charles" sort="Duyckaerts, Charles" uniqKey="Duyckaerts C" first="Charles" last="Duyckaerts">Charles Duyckaerts</name>
<affiliation wicri:level="3"><nlm:aff id="JCI36470">INSERM, UMR S679, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, Paris, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>INSERM, UMR S679, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI36470">Université Pierre et Marie Curie — Paris 06, UMR S679, Paris, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Université Pierre et Marie Curie — Paris 06, UMR S679, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Flavell, Richard A" sort="Flavell, Richard A" uniqKey="Flavell R" first="Richard A." last="Flavell">Richard A. Flavell</name>
<affiliation wicri:level="2"><nlm:aff id="JCI36470">Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut</wicri:regionArea>
<placeName><region type="state">Connecticut</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="JCI36470">Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut</wicri:regionArea>
<placeName><region type="state">Connecticut</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Hirsch, Etienne C" sort="Hirsch, Etienne C" uniqKey="Hirsch E" first="Etienne C." last="Hirsch">Etienne C. Hirsch</name>
<affiliation wicri:level="3"><nlm:aff id="JCI36470">INSERM, UMR S679, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, Paris, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>INSERM, UMR S679, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI36470">Université Pierre et Marie Curie — Paris 06, UMR S679, Paris, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Université Pierre et Marie Curie — Paris 06, UMR S679, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Hunot, Stephane" sort="Hunot, Stephane" uniqKey="Hunot S" first="Stéphane" last="Hunot">Stéphane Hunot</name>
<affiliation wicri:level="3"><nlm:aff id="JCI36470">INSERM, UMR S679, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, Paris, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>INSERM, UMR S679, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="JCI36470">Université Pierre et Marie Curie — Paris 06, UMR S679, Paris, France.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">France</country>
<wicri:regionArea>Université Pierre et Marie Curie — Paris 06, UMR S679, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">The Journal of Clinical Investigation</title>
<idno type="ISSN">0021-9738</idno>
<idno type="eISSN">1558-8238</idno>
<imprint><date when="2008">2008</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aged</term>
<term>Aged, 80 and over</term>
<term>Animals</term>
<term>Brain (cytology)</term>
<term>Brain (immunology)</term>
<term>Brain (pathology)</term>
<term>CD4-Positive T-Lymphocytes (cytology)</term>
<term>CD4-Positive T-Lymphocytes (immunology)</term>
<term>Cell Death (physiology)</term>
<term>Disease Models, Animal</term>
<term>Dopamine (metabolism)</term>
<term>Fas Ligand Protein (genetics)</term>
<term>Fas Ligand Protein (metabolism)</term>
<term>Homeodomain Proteins (genetics)</term>
<term>Homeodomain Proteins (metabolism)</term>
<term>Humans</term>
<term>Immune System (physiology)</term>
<term>Interferon-gamma (metabolism)</term>
<term>Male</term>
<term>Mice</term>
<term>Mice, Inbred C57BL</term>
<term>Mice, Knockout</term>
<term>Nerve Degeneration (immunology)</term>
<term>Nerve Degeneration (pathology)</term>
<term>Neurons (cytology)</term>
<term>Neurons (metabolism)</term>
<term>Neurons (pathology)</term>
<term>Parkinson Disease (immunology)</term>
<term>Parkinson Disease (pathology)</term>
<term>Parkinsonian Disorders (immunology)</term>
<term>Parkinsonian Disorders (pathology)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Fas Ligand Protein</term>
<term>Homeodomain Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Dopamine</term>
<term>Fas Ligand Protein</term>
<term>Homeodomain Proteins</term>
<term>Interferon-gamma</term>
</keywords>
<keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Brain</term>
<term>CD4-Positive T-Lymphocytes</term>
<term>Neurons</term>
</keywords>
<keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Brain</term>
<term>CD4-Positive T-Lymphocytes</term>
<term>Nerve Degeneration</term>
<term>Parkinson Disease</term>
<term>Parkinsonian Disorders</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Neurons</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Brain</term>
<term>Nerve Degeneration</term>
<term>Neurons</term>
<term>Parkinson Disease</term>
<term>Parkinsonian Disorders</term>
</keywords>
<keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Cell Death</term>
<term>Immune System</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Aged</term>
<term>Aged, 80 and over</term>
<term>Animals</term>
<term>Disease Models, Animal</term>
<term>Humans</term>
<term>Male</term>
<term>Mice</term>
<term>Mice, Inbred C57BL</term>
<term>Mice, Knockout</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of dopamine-containing neurons. Mounting evidence suggests that dopaminergic cell death is influenced by the innate immune system. However, the pathogenic role of the adaptive immune system in PD remains enigmatic. Here we showed that CD8<sup>+</sup>
and CD4<sup>+</sup>
T cells but not B cells had invaded the brain in both postmortem human PD specimens and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD during the course of neuronal degeneration. We further demonstrated that MPTP-induced dopaminergic cell death was markedly attenuated in the absence of mature T lymphocytes in 2 different immunodeficient mouse strains (<italic>Rag1<sup>–/–</sup>
</italic>
and <italic>Tcrb<sup>–/–</sup>
</italic>
mice). Importantly, similar attenuation of MPTP-induced dopaminergic cell death was seen in mice lacking CD4 as well as in <italic>Rag1<sup>–/–</sup>
</italic>
mice reconstituted with FasL-deficient splenocytes. However, mice lacking CD8 and <italic>Rag1<sup>–/–</sup>
</italic>
mice reconstituted with IFN-γ–deficient splenocytes were not protected. These data indicate that T cell–mediated dopaminergic toxicity is almost exclusively arbitrated by CD4<sup>+</sup>
T cells and requires the expression of FasL but not IFNγ. Further, our data may provide a rationale for targeting the adaptive arm of the immune system as a therapeutic strategy in PD.
</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>France</li>
<li>États-Unis</li>
</country>
<region><li>Connecticut</li>
<li>Île-de-France</li>
</region>
<settlement><li>Paris</li>
</settlement>
</list>
<tree><country name="France"><region name="Île-de-France"><name sortKey="Brochard, Vanessa" sort="Brochard, Vanessa" uniqKey="Brochard V" first="Vanessa" last="Brochard">Vanessa Brochard</name>
</region>
<name sortKey="Alvarez Fischer, Daniel" sort="Alvarez Fischer, Daniel" uniqKey="Alvarez Fischer D" first="Daniel" last="Alvarez-Fischer">Daniel Alvarez-Fischer</name>
<name sortKey="Alvarez Fischer, Daniel" sort="Alvarez Fischer, Daniel" uniqKey="Alvarez Fischer D" first="Daniel" last="Alvarez-Fischer">Daniel Alvarez-Fischer</name>
<name sortKey="Beray Berthat, Virginie" sort="Beray Berthat, Virginie" uniqKey="Beray Berthat V" first="Virginie" last="Beray-Berthat">Virginie Beray-Berthat</name>
<name sortKey="Beray Berthat, Virginie" sort="Beray Berthat, Virginie" uniqKey="Beray Berthat V" first="Virginie" last="Beray-Berthat">Virginie Beray-Berthat</name>
<name sortKey="Bonduelle, Olivia" sort="Bonduelle, Olivia" uniqKey="Bonduelle O" first="Olivia" last="Bonduelle">Olivia Bonduelle</name>
<name sortKey="Brochard, Vanessa" sort="Brochard, Vanessa" uniqKey="Brochard V" first="Vanessa" last="Brochard">Vanessa Brochard</name>
<name sortKey="Callebert, Jacques" sort="Callebert, Jacques" uniqKey="Callebert J" first="Jacques" last="Callebert">Jacques Callebert</name>
<name sortKey="Combadiere, Behazine" sort="Combadiere, Behazine" uniqKey="Combadiere B" first="Béhazine" last="Combadière">Béhazine Combadière</name>
<name sortKey="Duyckaerts, Charles" sort="Duyckaerts, Charles" uniqKey="Duyckaerts C" first="Charles" last="Duyckaerts">Charles Duyckaerts</name>
<name sortKey="Duyckaerts, Charles" sort="Duyckaerts, Charles" uniqKey="Duyckaerts C" first="Charles" last="Duyckaerts">Charles Duyckaerts</name>
<name sortKey="Hirsch, Etienne C" sort="Hirsch, Etienne C" uniqKey="Hirsch E" first="Etienne C." last="Hirsch">Etienne C. Hirsch</name>
<name sortKey="Hirsch, Etienne C" sort="Hirsch, Etienne C" uniqKey="Hirsch E" first="Etienne C." last="Hirsch">Etienne C. Hirsch</name>
<name sortKey="Hunot, Stephane" sort="Hunot, Stephane" uniqKey="Hunot S" first="Stéphane" last="Hunot">Stéphane Hunot</name>
<name sortKey="Hunot, Stephane" sort="Hunot, Stephane" uniqKey="Hunot S" first="Stéphane" last="Hunot">Stéphane Hunot</name>
<name sortKey="Launay, Jean Marie" sort="Launay, Jean Marie" uniqKey="Launay J" first="Jean-Marie" last="Launay">Jean-Marie Launay</name>
<name sortKey="Perrin, Aline" sort="Perrin, Aline" uniqKey="Perrin A" first="Aline" last="Perrin">Aline Perrin</name>
<name sortKey="Perrin, Aline" sort="Perrin, Aline" uniqKey="Perrin A" first="Aline" last="Perrin">Aline Perrin</name>
<name sortKey="Prigent, Annick" sort="Prigent, Annick" uniqKey="Prigent A" first="Annick" last="Prigent">Annick Prigent</name>
<name sortKey="Prigent, Annick" sort="Prigent, Annick" uniqKey="Prigent A" first="Annick" last="Prigent">Annick Prigent</name>
</country>
<country name="États-Unis"><region name="Connecticut"><name sortKey="Laouar, Yasmina" sort="Laouar, Yasmina" uniqKey="Laouar Y" first="Yasmina" last="Laouar">Yasmina Laouar</name>
</region>
<name sortKey="Flavell, Richard A" sort="Flavell, Richard A" uniqKey="Flavell R" first="Richard A." last="Flavell">Richard A. Flavell</name>
<name sortKey="Flavell, Richard A" sort="Flavell, Richard A" uniqKey="Flavell R" first="Richard A." last="Flavell">Richard A. Flavell</name>
</country>
</tree>
</affiliations>
</record>
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