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

38 Citations (Scopus)

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

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T-Lymphocytes
Peptides
Membranes
Regulatory T-Lymphocytes
Immunosuppressive Agents
Phosphorylation
Proteins
Immunoglobulin Domains

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Fornasa, G., Groyer, E., Clement, M., Dimitrov, J., Compain, C., Gaston, A. T., ... 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

TCR stimulation drives cleavage and shedding of the ITIM receptor CD31. / Fornasa, Giulia; Groyer, Emilie; Clement, Marc; Dimitrov, Jordan; Compain, Caroline; Gaston, Anh Thu; Varthaman, Aditi; Khallou-Laschet, Jamila; Newman, Debra K.; Graff-Dubois, Stéphanie; Nicoletti, Antonino; Caligiuri, Giuseppina.

In: Journal of Immunology, Vol. 184, No. 10, 15.05.2010, p. 5485-5492.

Research output: Contribution to journalArticle

Fornasa, G, Groyer, E, Clement, M, Dimitrov, J, Compain, C, Gaston, AT, Varthaman, A, Khallou-Laschet, J, Newman, DK, Graff-Dubois, S, Nicoletti, A & Caligiuri, G 2010, 'TCR stimulation drives cleavage and shedding of the ITIM receptor CD31', Journal of Immunology, vol. 184, no. 10, pp. 5485-5492. https://doi.org/10.4049/jimmunol.0902219
Fornasa G, Groyer E, Clement M, Dimitrov J, Compain C, Gaston AT et al. TCR stimulation drives cleavage and shedding of the ITIM receptor CD31. Journal of Immunology. 2010 May 15;184(10):5485-5492. https://doi.org/10.4049/jimmunol.0902219
Fornasa, Giulia ; Groyer, Emilie ; Clement, Marc ; Dimitrov, Jordan ; Compain, Caroline ; Gaston, Anh Thu ; Varthaman, Aditi ; Khallou-Laschet, Jamila ; Newman, Debra K. ; Graff-Dubois, Stéphanie ; Nicoletti, Antonino ; Caligiuri, Giuseppina. / TCR stimulation drives cleavage and shedding of the ITIM receptor CD31. In: Journal of Immunology. 2010 ; Vol. 184, No. 10. pp. 5485-5492.
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