Upholding the T cell immune-regulatory function of CD31 inhibits the formation of T/B immunological synapses invitro and attenuates the development of experimental autoimmune arthritis in vivo

Marc Clement, Giulia Fornasa, Stéphane Loyau, Marion Morvan, Francesco Andreata, Kevin Guedj, Jamila Khallou-Laschet, Paola Larghi, Delphine Le Roux, Georges Bismuth, Gilles Chiocchia, Claire Hivroz, Debra K. Newman, Antonino Nicoletti, Giuseppina Caligiuri

Research output: Contribution to journalArticle

Abstract

CD31, a trans-homophilic inhibitory receptor expressed on both T- and B-lymphocytes, drives the mutual detachment of interacting leukocytes. Intriguingly, T cell CD31 molecules relocate to the immunological synapse (IS), where the T and B cells establish a stable interaction.Here, we show that intact CD31 molecules, which are able to drive an inhibitory signal, are concentrated at the periphery of the IS but are excluded from the center of the IS. At this site, were the cells establish the closest contact, the CD31 molecules are cleaved, and most of the extracellular portion of the protein, including the trans-homophilic binding sites, is shed from the cell surface.T cells lacking CD31 trans-homophilic binding sites easily establish stable interactions with B cells; at the opposite, CD31 signaling agonists inhibit T/B IS formation as well as the ensuing helper T cell activation and function. Confocal microscopy and flow cytometry analysis of experimental T/B IS shows that the T cell inhibitory effects of CD31 agonists depend on SHP-2 signaling, which reduces the phosphorylation of ZAP70.The analysis of synovial tissue biopsies from patients affected by rheumatoid arthritis showed that T cell CD31 molecules are excluded from the center of the T/B cell synapses invivo. Interestingly, the administration of CD31 agonists invivo significantly attenuated the development of the clinical signs of collagen-induced arthritis in DBA1/J mice.Altogether, our data indicate that the T cell co-inhibitory receptor CD31 prevents the formation of functional T/B immunological synapses and that therapeutic strategies aimed at sustaining CD31 signaling will attenuate the development of autoimmune responses invivo.

Original languageEnglish
Pages (from-to)23-33
Number of pages11
JournalJournal of Autoimmunity
Volume56
DOIs
Publication statusPublished - Jan 1 2015

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Immunological Synapses
Experimental Arthritis
Regulatory T-Lymphocytes
T-Lymphocytes
B-Lymphocytes
Costimulatory and Inhibitory T-Cell Receptors
Binding Sites
Helper-Inducer T-Lymphocytes
Autoimmunity
Confocal Microscopy
Synapses
Rheumatoid Arthritis
Flow Cytometry
Leukocytes
Phosphorylation
Biopsy

Keywords

  • Autoimmune arthritis
  • CD31
  • Immunological synapse
  • Inhibitory receptors
  • ITIM
  • T lymphocytes

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Medicine(all)

Cite this

Upholding the T cell immune-regulatory function of CD31 inhibits the formation of T/B immunological synapses invitro and attenuates the development of experimental autoimmune arthritis in vivo. / Clement, Marc; Fornasa, Giulia; Loyau, Stéphane; Morvan, Marion; Andreata, Francesco; Guedj, Kevin; Khallou-Laschet, Jamila; Larghi, Paola; Le Roux, Delphine; Bismuth, Georges; Chiocchia, Gilles; Hivroz, Claire; Newman, Debra K.; Nicoletti, Antonino; Caligiuri, Giuseppina.

In: Journal of Autoimmunity, Vol. 56, 01.01.2015, p. 23-33.

Research output: Contribution to journalArticle

Clement, M, Fornasa, G, Loyau, S, Morvan, M, Andreata, F, Guedj, K, Khallou-Laschet, J, Larghi, P, Le Roux, D, Bismuth, G, Chiocchia, G, Hivroz, C, Newman, DK, Nicoletti, A & Caligiuri, G 2015, 'Upholding the T cell immune-regulatory function of CD31 inhibits the formation of T/B immunological synapses invitro and attenuates the development of experimental autoimmune arthritis in vivo', Journal of Autoimmunity, vol. 56, pp. 23-33. https://doi.org/10.1016/j.jaut.2014.09.002
Clement, Marc ; Fornasa, Giulia ; Loyau, Stéphane ; Morvan, Marion ; Andreata, Francesco ; Guedj, Kevin ; Khallou-Laschet, Jamila ; Larghi, Paola ; Le Roux, Delphine ; Bismuth, Georges ; Chiocchia, Gilles ; Hivroz, Claire ; Newman, Debra K. ; Nicoletti, Antonino ; Caligiuri, Giuseppina. / Upholding the T cell immune-regulatory function of CD31 inhibits the formation of T/B immunological synapses invitro and attenuates the development of experimental autoimmune arthritis in vivo. In: Journal of Autoimmunity. 2015 ; Vol. 56. pp. 23-33.
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abstract = "CD31, a trans-homophilic inhibitory receptor expressed on both T- and B-lymphocytes, drives the mutual detachment of interacting leukocytes. Intriguingly, T cell CD31 molecules relocate to the immunological synapse (IS), where the T and B cells establish a stable interaction.Here, we show that intact CD31 molecules, which are able to drive an inhibitory signal, are concentrated at the periphery of the IS but are excluded from the center of the IS. At this site, were the cells establish the closest contact, the CD31 molecules are cleaved, and most of the extracellular portion of the protein, including the trans-homophilic binding sites, is shed from the cell surface.T cells lacking CD31 trans-homophilic binding sites easily establish stable interactions with B cells; at the opposite, CD31 signaling agonists inhibit T/B IS formation as well as the ensuing helper T cell activation and function. Confocal microscopy and flow cytometry analysis of experimental T/B IS shows that the T cell inhibitory effects of CD31 agonists depend on SHP-2 signaling, which reduces the phosphorylation of ZAP70.The analysis of synovial tissue biopsies from patients affected by rheumatoid arthritis showed that T cell CD31 molecules are excluded from the center of the T/B cell synapses invivo. Interestingly, the administration of CD31 agonists invivo significantly attenuated the development of the clinical signs of collagen-induced arthritis in DBA1/J mice.Altogether, our data indicate that the T cell co-inhibitory receptor CD31 prevents the formation of functional T/B immunological synapses and that therapeutic strategies aimed at sustaining CD31 signaling will attenuate the development of autoimmune responses invivo.",
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AU - Loyau, Stéphane

AU - Morvan, Marion

AU - Andreata, Francesco

AU - Guedj, Kevin

AU - Khallou-Laschet, Jamila

AU - Larghi, Paola

AU - Le Roux, Delphine

AU - Bismuth, Georges

AU - Chiocchia, Gilles

AU - Hivroz, Claire

AU - Newman, Debra K.

AU - Nicoletti, Antonino

AU - Caligiuri, Giuseppina

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