1. TCR stimulation drives cleavage and shedding of the ITIM receptor CD31.
- Author
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Fornasa G, Groyer E, Clement M, Dimitrov J, Compain C, Gaston AT, Varthaman A, Khallou-Laschet J, Newman DK, Graff-Dubois S, Nicoletti A, and Caligiuri G
- Subjects
- Amino Acid Sequence, Animals, Cell Membrane immunology, Cell Membrane metabolism, Cells, Cultured, Extracellular Space immunology, Extracellular Space metabolism, Humans, Immunoglobulins metabolism, Jurkat Cells, Lymphocyte Activation immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Data, Peptide Fragments chemical synthesis, Peptide Fragments genetics, Platelet Endothelial Cell Adhesion Molecule-1 biosynthesis, Platelet Endothelial Cell Adhesion Molecule-1 genetics, Protein Structure, Tertiary, Peptide Fragments metabolism, Platelet Endothelial Cell Adhesion Molecule-1 metabolism, Receptors, Antigen, T-Cell metabolism, Receptors, Antigen, T-Cell physiology, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism
- Abstract
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
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