TCR stimulation drives cleavage and shedding of the ITIM receptor CD31.

Giulia Fornasa (1) , Emilie Groyer (1) , Marc Clement (1) , Jordan Dimitrov (2) , Caroline Compain (1) , Anh-Thu Gaston (1) , Aditi Varthaman (1) , Jamila Khallou-Laschet (1) , Debra K. Newman (3) , Stéphanie Graff-Dubois (1, 4) , Antonino Nicoletti (1) , Giuseppina Caligiuri (1)

1 LBPC (U698) - Hémostase, bio-ingénierie et remodelage cardiovasculaires
2 CRC (UMR_S 872) - Centre de Recherche des Cordeliers
3 Blood Research Institute
4 Immunité et Infection

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.

Domaines: Immunologie

Giulia Fornasa, Emilie Groyer, Marc Clement, Jordan Dimitrov, Caroline Compain, et al.. TCR stimulation drives cleavage and shedding of the ITIM receptor CD31.: CD31 cleavage and shedding from TCR-stimulated T-cells. Journal of Immunology, 2010, 184 (10), pp.5485-92. ⟨10.4049/jimmunol.0902219⟩. ⟨inserm-00512366⟩