TCR stimulation drives cleavage and shedding of the ITIM receptor CD31

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

Research output: Contribution to journalArticle

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 CD31shed cells. However, we show that a juxta-membrane extracellular sequence, comprising part of the domain 6, remains expressed at the surface of CD31shed 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.

Original languageEnglish
Pages (from-to)5485-5492
Number of pages8
JournalJournal of Immunology
Volume184
Issue number10
DOIs
Publication statusPublished - May 15 2010

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

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    Fornasa, G., Groyer, E., Clement, M., Dimitrov, J., Compain, C., Gaston, A. T., Varthaman, A., Khallou-Laschet, J., Newman, D. K., Graff-Dubois, S., Nicoletti, A., & Caligiuri, G. (2010). TCR stimulation drives cleavage and shedding of the ITIM receptor CD31. Journal of Immunology, 184(10), 5485-5492. https://doi.org/10.4049/jimmunol.0902219