Lymphocyte Cell-Cycle Inhibition by HLA-G Is Mediated by Phosphatase SHP-2 and Acts on the mTOR Pathway
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{"title"=>"Lymphocyte cell-cycle inhibition by HLA-G is mediated by phosphatase SHP-2 and acts on the mTOR pathway", "type"=>"journal", "authors"=>[{"first_name"=>"Farah", "last_name"=>"Ketroussi", "scopus_author_id"=>"40561303800"}, {"first_name"=>"Massimo", "last_name"=>"Giuliani", "scopus_author_id"=>"35789069800"}, {"first_name"=>"Rajia", "last_name"=>"Bahri", "scopus_author_id"=>"8041937700"}, {"first_name"=>"Bruno", "last_name"=>"Azzarone", "scopus_author_id"=>"7006615101"}, {"first_name"=>"Bernard", "last_name"=>"Charpentier", "scopus_author_id"=>"7102912631"}, {"first_name"=>"Antoine", "last_name"=>"Durrbach", "scopus_author_id"=>"34975077600"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "pui"=>"362405463", "sgr"=>"80051973196", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "scopus"=>"2-s2.0-80051973196", "pmid"=>"21887223", "doi"=>"10.1371/journal.pone.0022776"}, "id"=>"e345d0bd-92f1-3e1e-aa67-02740fe9d9f3", "abstract"=>"Human leukocyte antigen G (HLA-G) is involved in regulating T-cell responses through its interaction with inhibitory receptors belonging to the immunoglobulin-like transcript family (ILT). In this context, we investigated the pathways involved in the control of cell-cycle entry of T cells following HLA-G interaction with its inhibitory receptor. We show that HLA-G acts through its interaction with the LILRB1 receptor expressed on T lymphocytes. Both HLA-G and LILRB1 antibodies block the inhibitory effect of HLA-G and restore T-cell proliferation. The interaction of HLA-G with T lymphocytes is associated with phosphorylation of SHP-2 phosphatase, but not SHP-1. In addition, in activated T cells, their incubation with HLA-G is not associated with a decrease in the TCR or CD28 downstream pathways, but is associated with dephosphorylation of the mTOR molecule and p70S6K. In contrast, Akt, which acts upstream of mTOR, is not affected by HLA-G. The inhibition of SHP-2 by NSC-87877(5 microM), a chemical inhibitor of SHP-2, or the use of siRNA, abrogates dephosphorylation of mTOR and impairs the overexpression of p27(kip) in the presence of HLA-G. Together, these results indicate that HLA-G is associated with activation of phosphatase SHP-2, which inhibits the mTOR pathway and favors the inhibition of the cell-cycle entry of human-activated T cells.", "link"=>"http://www.mendeley.com/research/lymphocyte-cellcycle-inhibition-hlag-mediated-phosphatase-shp2-acts-mtor-pathway", "reader_count"=>27, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>2, "Student > Doctoral Student"=>2, "Researcher"=>4, "Student > Ph. D. Student"=>11, "Other"=>3, "Student > Master"=>1, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>2, "Student > Doctoral Student"=>2, "Researcher"=>4, "Student > Ph. D. Student"=>11, "Other"=>3, "Student > Master"=>1, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>4, "Agricultural and Biological Sciences"=>15, "Medicine and Dentistry"=>3, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>15}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"United Kingdom"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/742979"], "description"=>"<p>Determination by Western Blot of the expression of SHP-1, p-SHP-1 (A), and p-CD3ξ, p-ERK, p-JNK, and p-P38 (B) following incubation of activated T cells with OKT3/IL2 in the presence of HLA-G5-coated beads.</p>", "links"=>[], "tags"=>["blot", "p-shp-1", "p-p38", "incubation", "activated", "cells", "hla-g5-coated"], "article_id"=>413344, "categories"=>["Immunology"], "users"=>["Farah Ketroussi", "Massimo Giuliani", "Rajia Bahri", "Bruno Azzarone", "Bernard Charpentier", "Antoine Durrbach"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0022776.g003", "stats"=>{"downloads"=>2, "page_views"=>126, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Determination_by_Western_Blot_of_the_expression_of_SHP_1_p_SHP_1_A_and_p_CD3_958_p_ERK_p_JNK_and_p_P38_B_following_incubation_of_activated_T_cells_with_OKT3_IL2_in_the_presence_of_HLA_G5_coated_beads_/413344", "title"=>"Determination by Western Blot of the expression of SHP-1, p-SHP-1 (A), and p-CD3ξ, p-ERK, p-JNK, and p-P38 (B) following incubation of activated T cells with OKT3/IL2 in the presence of HLA-G5-coated beads.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-24 00:55:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/374566", "https://ndownloader.figshare.com/files/374606"], "description"=>"<div><p>Human leukocyte antigen G (HLA-G) is involved in regulating T-cell responses through its interaction with inhibitory receptors belonging to the immunoglobulin-like transcript family (ILT). In this context, we investigated the pathways involved in the control of cell-cycle entry of T cells following HLA-G interaction with its inhibitory receptor. We show that HLA-G acts through its interaction with the LILRB1 receptor expressed on T lymphocytes. Both HLA-G and LILRB1 antibodies block the inhibitory effect of HLA-G and restore T-cell proliferation. The interaction of HLA-G with T lymphocytes is associated with phosphorylation of SHP-2 phosphatase, but not SHP-1. In addition, in activated T cells, their incubation with HLA-G is not associated with a decrease in the TCR or CD28 downstream pathways, but is associated with dephosphorylation of the mTOR molecule and p70S6K. In contrast, Akt, which acts upstream of mTOR, is not affected by HLA-G. The inhibition of SHP-2 by NSC-87877(5 µM), a chemical inhibitor of SHP-2, or the use of siRNA, abrogates dephosphorylation of mTOR and impairs the overexpression of p27<sup>kip</sup> in the presence of HLA-G. Together, these results indicate that HLA-G is associated with activation of phosphatase SHP-2, which inhibits the mTOR pathway and favors the inhibition of the cell-cycle entry of human-activated T cells.</p> </div>", "links"=>[], "tags"=>["lymphocyte", "cell-cycle", "inhibition", "hla-g", "mediated", "phosphatase", "shp-2", "acts", "mtor", "pathway"], "article_id"=>133963, "categories"=>["Immunology"], "users"=>["Farah Ketroussi", "Massimo Giuliani", "Rajia Bahri", "Bruno Azzarone", "Bernard Charpentier", "Antoine Durrbach"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0022776.s001", "https://dx.doi.org/10.1371/journal.pone.0022776.s002"], "stats"=>{"downloads"=>2, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Lymphocyte_Cell_Cycle_Inhibition_by_HLA_G_Is_Mediated_by_Phosphatase_SHP_2_and_Acts_on_the_mTOR_Pathway/133963", "title"=>"Lymphocyte Cell-Cycle Inhibition by HLA-G Is Mediated by Phosphatase SHP-2 and Acts on the mTOR Pathway", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-08-24 01:06:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/742795"], "description"=>"<p>T cells were stimulated with OKT3/IL2, and were incubated with HLA-G5-coated beads for 0, 15 or 30 min. After cell lysis, LILRB1, SHP-1, or SHP-2 were immuno-purified and the co-precipitated molecules were submitted to gel electrophoresis and then transferred to a PVDF membrane. SHP-1, SHP-2, and LILRB1 were detected by western-blot analysis. <b>A</b>: Immunoprecipitation of LILRB1. LILRB1, SHP-1 and SHP-2 were detected by western blot. The ratio of SHP-1 or SHP-2/LILRB1 have been determined by densitometry. <b>B</b>: Immunoprecipitation of SHP-1. LILRB1 and SHP-1 were detected by western blot. The ratio of LILRB1/SHP-1 has been determined by densitometry. C Immunoprecipitation of SHP-2. LILRB1 and SHP-2 were detected by western blot. The ratio of LILRB1/SHP-2 has been determined by densitometry.</p>", "links"=>[], "tags"=>["shp-2", "cells"], "article_id"=>413169, "categories"=>["Immunology"], "users"=>["Farah Ketroussi", "Massimo Giuliani", "Rajia Bahri", "Bruno Azzarone", "Bernard Charpentier", "Antoine Durrbach"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0022776.g002", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Immuno_precipitation_of_ILT_2_SHP_1_or_SHP_2_in_T_cells_in_the_presence_or_absence_of_HLA_G_/413169", "title"=>"Immuno-precipitation of ILT-2, SHP-1, or SHP-2 in T cells in the presence or absence of HLA-G.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-24 00:52:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/743173"], "description"=>"<p>Activated T cells were transfected with siRNA against SHP or a siRNA control, and submitted 48 h later to gel electrophoresis. SHP-2 was determined by western blotting. siRNA transfected against SHP-2 resulted in a dramatic reduction of SHP-2. <b>B</b>: Transcriptional and functional inhibition of SHP-2 with siRNA against SHP-2 or with the specific inhibitor of SHP-2 (NSC-87877) in T cells in the presence of HLA-G5-coated beads. In activated T lymphocytes transfected with siRNA–SHP-2 or incubated with NSC-87877, incubation with HLAG5-coated beads was not associated with mTOR dephosphorylation. <b>C</b>: The ratio of p-mTOR/actin has been determined by densitometry <b>D</b>: Effect of HLA-G5 on p27<sup>kip</sup> after inhibition of SHP-2. Stimulated T cells were transfected with siRNA–SHP-2 or control siRNA (siRNA ctrl) and incubated with HLA-G5-coated beads for 24 h. In T lymphocytes transfected with siRNA against SHP-2 (siRNA-SHP-2), p27<sup>kip</sup> did not appear following incubation with HLA-G5, whereas it was observed in T cells transfected with siRNA–control.</p>", "links"=>[], "tags"=>["transcriptional", "inhibition", "shp-2", "sirna"], "article_id"=>413547, "categories"=>["Immunology"], "users"=>["Farah Ketroussi", "Massimo Giuliani", "Rajia Bahri", "Bruno Azzarone", "Bernard Charpentier", "Antoine Durrbach"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0022776.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_Transcriptional_inhibition_of_SHP_2_with_siRNA_against_SHP_2_/413547", "title"=>"A: Transcriptional inhibition of SHP-2 with siRNA against SHP-2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-24 00:59:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/743061"], "description"=>"<p>T lymphocytes were activated before incubation with OKT3/IL-2 for 72 h. In the presence of HLA-G, p-mTOR and p70S6K were transiently dephosphorylated, but Akt was not. This result correlates with SHP-2 phosphorylation. <b>B</b>: Intracellular distribution of ILT-2 and SHP-2 in the presence of HLA-G as assessed by immunofluorescence. In stimulated T cells incubated with HLA-G5-coated beads, SHP-2 was redistributed intracellularly and translocated from the nucleus to the cytoplasm, whereas it was only partially redistributed after 1 h with LILRB1.</p>", "links"=>[], "tags"=>["time-course", "modification", "p70s6k", "activated", "cells", "incubated", "hla-g5-coated"], "article_id"=>413427, "categories"=>["Immunology"], "users"=>["Farah Ketroussi", "Massimo Giuliani", "Rajia Bahri", "Bruno Azzarone", "Bernard Charpentier", "Antoine Durrbach"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0022776.g004", "stats"=>{"downloads"=>3, "page_views"=>72, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_Time_course_modification_of_pSHP_2_p_Akt_p_mTOR_and_p70S6K_on_activated_T_cells_incubated_with_HLA_G5_coated_beads_/413427", "title"=>"A: Time-course modification of pSHP-2, p-Akt, p-mTOR, and p70S6K on activated T cells incubated with HLA-G5-coated beads.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-24 00:57:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/742688"], "description"=>"<p><b>A</b>: Scheme of the interaction between 4H84 coated beads with HLA-G5. <b>B</b>: Cell surface expression of LILRB1 on lymphocytes analyzed by FASC using the CD85J mAb. The isotype control mAb was tested on resting T cells (Iso). LILRB1 is expressed both on resting and activated T cells. <b>C</b>: Thymidine incorporation into T cells stimulated with OKT3/IL2 and incubated or not with HLA-G- or LILRB1-blocking antibodies or the HLA-G-blocking antibody (87G) <b>D</b>: The inhibition of T-cell proliferation associated with HLA-G5 was dramatically reduced when the HLA-G-inhibitory mAb(87G)- or LILRB1-blocking antibody were added to T cells in the presence of HLA-G.</p>", "links"=>[], "tags"=>["proliferation", "cells", "stimulated", "hla-g-", "lilrb1-blocking"], "article_id"=>413057, "categories"=>["Immunology"], "users"=>["Farah Ketroussi", "Massimo Giuliani", "Rajia Bahri", "Bruno Azzarone", "Bernard Charpentier", "Antoine Durrbach"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0022776.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibition_of_proliferation_of_T_cells_stimulated_with_OKT3_IL2_in_the_presence_or_absence_of_HLA_G_and_with_or_without_HLA_G_or_LILRB1_blocking_antibodies_/413057", "title"=>"Inhibition of proliferation of T cells stimulated with OKT3/IL2 in the presence or absence of HLA-G, and with or without HLA-G- or LILRB1-blocking antibodies.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-24 00:50:57"}

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Relative Metric

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