1. TCR stimulation drives cleavage and shedding of the ITIM receptor CD31
- Author
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Fornasa, Giulia, Groyer, Emilie, Clement, Marc, Dimitrov, Jordan, Compain, Caroline, Gaston, Anh-Thu, Varthaman, Aditi, Khallou-Laschet, Jamila, Newman, Debra, Graff-Dubois, Stéphanie, Nicoletti, Antonino, Caligiuri, Giuseppina, Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Blood Research Institute, BloodCenter of Wisconsin, Immunité et Infection, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR113-Université Pierre et Marie Curie - Paris 6 (UPMC), This work was supported in part by grants from the 'Fondation de France' (Engt 2006-005656 and 2008- 002724), the 'Fondation pour la Recherche Médicale' (DCV20070409268) and the 'Agence Nationale de la Recherche' (project 'RELATE' and project 'BROSCI'). G.F. is the recipient of a training grant from the 'Ministère affaires étrangères' (Egide N°636511F) and of the 'Groupe de Reflexion sur la Recherche Cardio-vasculaire et la Féderation Française de Cardiologie'. E.G. was the recipient of a research grant from the 'Fondation pour la Recherche Médicale' (FDT20071211595)., ANR: project 'RELATE and 'BROSCI',project 'RELATE and 'BROSCI', Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), Hémostase, bio-ingénierie et remodelage cardiovasculaires ( LBPC ), Université Paris 13 ( UP13 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Galilée, Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR113-Institut National de la Santé et de la Recherche Médicale ( INSERM ), ANR : project 'RELATE and 'BROSCI',project 'RELATE and 'BROSCI', Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and ANR-07-PHYS-0021,RELATE,Regulation des lymphocytes dans les manifestations atherothrombotiques(2007)
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MESH : Molecular Sequence Data ,MESH: Immunoglobulins ,MESH : Cell Membrane ,MESH: Mice, Inbred BALB C ,MESH : Mice, Inbred C57BL ,MESH: Amino Acid Sequence ,MESH: T-Lymphocyte Subsets ,MESH: Mice, Knockout ,MESH : Receptors, Antigen, T-Cell ,MESH : Extracellular Space ,MESH : Immunoglobulins ,MESH: Protein Structure, Tertiary ,MESH: Mice, Inbred C57BL ,MESH : Mice ,MESH : Cells, Cultured ,MESH: Jurkat Cells ,[ SDV.IMM ] Life Sciences [q-bio]/Immunology ,MESH: Animals ,MESH: Peptide Fragments ,MESH: Lymphocyte Activation ,MESH: Mice ,MESH : Mice, Inbred BALB C ,MESH : Jurkat Cells ,MESH : Lymphocyte Activation ,MESH: Molecular Sequence Data ,MESH: Humans ,MESH : Amino Acid Sequence ,MESH : Peptide Fragments ,MESH : Humans ,MESH: Receptors, Antigen, T-Cell ,MESH: Antigens, CD31 ,MESH : T-Lymphocyte Subsets ,MESH: Extracellular Space ,MESH : Antigens, CD31 ,cardiovascular system ,MESH : Mice, Knockout ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,MESH : Animals ,MESH : Protein Structure, Tertiary ,MESH: Cell Membrane ,MESH: Cells, Cultured - Abstract
International audience; CD31 is a transmembrane molecule endowed with T cell regulatory functions owing to the presence of 2 immunotyrosine-based inhibitory motifs. For reasons not understood, CD31 is lost by a portion of circulating T lymphocytes, which appear prone to uncontrolled activation. In this study, we show that extracellular T cell CD31 comprising Ig-like domains 1 to 5 is cleaved and shed from the surface of human T cells upon activation via their TCR. The shed CD31 can be specifically detected as a soluble, truncated protein in human plasma. CD31 shedding results in the loss of its inhibitory function because the necessary cis-homo-oligomerization of the molecule, triggered by the trans-homophilic engagement of the distal Ig-like domain 1, cannot be established by CD31(shed) cells. However, we show that a juxta-membrane extracellular sequence, comprising part of the domain 6, remains expressed at the surface of CD31(shed) T cells. We also show that the immunosuppressive CD31 peptide aa 551-574 is highly homophilic and possibly acts by homo-oligomerizing with the truncated CD31 remaining after its cleavage and shedding. This peptide is able to sustain phosphorylation of the CD31 ITIM(686) and of SHP2 and to inhibit TCR-induced T cell activation. Finally, systemic administration of the peptide in BALB/c mice efficiently suppresses Ag-induced T cell-mediated immune responses in vivo. We conclude that the loss of T cell regulation caused by CD31 shedding driven by TCR stimulation can be rescued by molecular tools able to engage the truncated juxta-membrane extracellular molecule that remains exposed at the surface of CD31(shed) cells.
- Published
- 2010