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TCR stimulation drives cleavage and shedding of the ITIM receptor CD31.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2010 May 15; Vol. 184 (10), pp. 5485-92. Date of Electronic Publication: 2010 Apr 16. - Publication Year :
- 2010
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 184
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 20400708
- Full Text :
- https://doi.org/10.4049/jimmunol.0902219