TCR Stimulation Drives Cleavage and Shedding of the ITIM Receptor CD31

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

doi:10.4049/jimmunol.0902219

Cited by 63 publications

(74 citation statements)

References 38 publications

(38 reference statements)

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“…CD31-mediated homophilic interactions with antigen-presenting cells (APCs) regulate clonal T-cell expansion following priming, in line with recent reports (16). However, CD31 signaling only mildly affects memory T-cell division following antigen rechallenge, probably due to its lower expression by memory T cells, suggesting that the inhibitory effect of CD31 signaling acts at the level of T-cell priming.…”

Section: Discussionsupporting

confidence: 78%

Ig gene-like molecule CD31 plays a nonredundant role in the regulation of T-cell immunity and tolerance

Ma¹,

Mauro

Cornish³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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CD31 is an Ig-like molecule expressed by leukocytes and endothelial cells with an established role in the regulation of leukocyte trafficking. Despite genetic deletion of CD31 being associated with exacerbation of T cell-mediated autoimmunity, the contribution of this molecule to T-cell responses is largely unknown. Here we report that tumor and allograft rejection are significantly enhanced in CD31-deficient mice, which are also resistant to tolerance induction. We propose that these effects are dependent on an as yet unrecognized role for CD31-mediated homophilic interactions between T cells and antigen-presenting cells (APCs) during priming. We show that loss of CD31 interactions leads to enhanced primary clonal expansion, increased killing capacity, and diminished regulatory functions by T cells. Immunomodulation by CD31 signals correlates with a partial inhibition of proximal T-cell receptor (TCR) signaling, specifically Zap-70 phosphorylation. However, CD31-deficient mice do not develop autoimmunity due to increased T-cell death following activation, and we show that CD31 triggering induces Erkmediated prosurvival activity in T cells either in conjunction with TCR signaling or autonomously. We conclude that CD31 functions as a nonredundant comodulator of T-cell responses, which specializes in sizing the ensuing immune response by setting the threshold for Tcell activation and tolerance, while preventing memory T-cell death.costimulation | T-cell expansion | programmed cell death C D31, or platelet endothelial cell adhesion molecule-1 (PECAM-1) is a member of the Ig gene superfamily expressed at high density at the lateral borders of endothelial cells (ECs) and at a lower density on the surface of hematopoietic cells including T lymphocytes (1). By establishing homophilic interactions between apposing ECs and between the endothelium and migrating leukocytes, CD31 has been shown to contribute to EC: EC junctions and promote leukocyte transendothelial cell migration (TEM) (1).A number of in vivo models of T cell-mediated inflammation, including experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA), have implicated CD31-mediated interactions in the regulation of T-cell responses. Accelerated progression of EAE resulting in an early increased migration of mononuclear leukocyte infiltration into the central nervous system (CNS) and increased severity of CIA in mice lacking CD31 have been reported (2-4). As CD31 contributes to EC:EC junction integrity, the proinflammatory phenotype observed in these models has been attributed to vascular junction loosening in CD31-deficient endothelium (2, 5), rather than a direct effect on T-cell function.The expression of this molecule by both T cells and dendritic cells (6) suggests that CD31 is likely to be engaged in homophilic interactions during conventional antigen presentation. Indeed, CD31 engagement on T cells has the potential to directly affect TCR signaling (7-9). Despite these key observations, the role of CD31-mediated interactions i...

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Section: Discussionsupporting

confidence: 78%

Ig gene-like molecule CD31 plays a nonredundant role in the regulation of T-cell immunity and tolerance

Ma¹,

Mauro

Cornish³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Although a potential physiologic role of sCD31 serum levels in vivo remains to be determined, the membrane-anchored truncated protein remains capable of signaling (35); hence, the loss of the CD31 extracellular domain should not affect its ability to interfere with apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Activated inflammatory cells, including the endothelium, undergo active shedding of the extracellular domain of the CD31 molecule (34,35); this shedding could contribute to the loss of cell-cell adhesion (34) and to the rise in circulating soluble (s)CD31 during inflammatory diseases (35). Although a potential physiologic role of sCD31 serum levels in vivo remains to be determined, the membrane-anchored truncated protein remains capable of signaling (35); hence, the loss of the CD31 extracellular domain should not affect its ability to interfere with apoptosis.…”

Section: Discussionmentioning

confidence: 99%

CD31 signals confer immune privilege to the vascular endothelium

Cheung

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Constitutive resistance to cell death induced by inflammatory stimuli activating the extrinsic pathway of apoptosis is a key feature of vascular endothelial cells (ECs). Although this property is central to the maintenance of the endothelial barrier during inflammation, the molecular mechanisms of EC protection from cell-extrinsic, proapoptotic stimuli have not been investigated. We show that the Ig-family member CD31, which is expressed by endothelial but not epithelial cells, is necessary to prevent EC death induced by TNF-α and cytotoxic T lymphocytes in vitro. Combined quantitative RT-PCR array and biochemical analysis show that, upon the engagement of the TNF receptor with TNF-α on ECs, CD31 becomes activated and, in turn, counteracts the proapoptotic transcriptional program induced by TNF-α via activation of the Erk/Akt pathway. Specifically, Akt activation by CD31 signals prevents the localization of the forkhead transcription factor FoxO3 to the nucleus, thus inhibiting transcription of the proapoptotic genes CD95/Fas and caspase 7 and de-repressing the expression of the antiapoptotic gene cFlar. Both CD31 intracellular immunoreceptor tyrosinebased inhibition motifs are required for its prosurvival function. In vivo, CD31 gene transfer is sufficient to recapitulate the cytoprotective mechanisms in CD31 − pancreatic β cells, which become resistant to immune-mediated rejection when grafted in fully allogeneic recipients.endothelium | immunology | inflammation | lymphocytes | transplantation

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“…Second, loss of CD31 expression by memory T-cells is only apparent because this molecule is enzymatically shed, rather than transcriptionally downregulated (Fornasa et al, 2010). In fact, in memory T-cells, CD31 signaling can be triggered by cell polarization and subsequent clustering on the same cell membrane , and CD31 activity after shedding can be recovered by a peptide (containing CD31 amino acid residues 551 to 574) that is able to homo-oligomerize with the truncated CD31 fragment (Fornasa et al, 2010).…”

Section: Cd31 Is a Non-redundant Co-modulator Of T-cell Immunitymentioning

confidence: 99%

“…In fact, in memory T-cells, CD31 signaling can be triggered by cell polarization and subsequent clustering on the same cell membrane , and CD31 activity after shedding can be recovered by a peptide (containing CD31 amino acid residues 551 to 574) that is able to homo-oligomerize with the truncated CD31 fragment (Fornasa et al, 2010). In addition, human memory T-cells have been shown to acquire CD31 expression following trans-endothelial migration (TEM) as a result of membrane transfer from ECs in vitro (Brezinschek et al, 1999).…”

Section: Cd31 Is a Non-redundant Co-modulator Of T-cell Immunitymentioning

confidence: 99%

An immunologist's guide to CD31 function in T-cells

Marelli‐Berg

Clément

Mauro

et al. 2013

Journal of Cell Science

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116

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SummaryAlthough it is expressed by all leukocytes, including T-, B-lymphocytes and dendritic cells, the immunoglobulin-like receptor CD31 is generally regarded by immunologists as a marker of endothelial cell lineage that lacks an established functional role in adaptive immunity. This perception has recently been challenged by studies that reveal a key role for this molecule in the regulation of T-cell homeostasis, effector function and trafficking. The complexity of the biological functions of CD31 results from the integration of its adhesive and signaling functions in both the immune and vascular systems. Signaling by means of CD31 is induced by homophilic engagement during the interactions of immune cells and is mediated by phosphatase recruitment or activation through immunoreceptor tyrosine inhibitory motifs (ITIMs) that are located in its cytoplasmic tail. Loss of CD31 function is associated with excessive immunoreactivity and susceptibility to cytotoxic killing. Here, we discuss recent findings that have brought to light a non-redundant, complex role for this molecule in the regulation of T-cell-mediated immune responses, with large impact on our understanding of immunity in health and disease.

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TCR Stimulation Drives Cleavage and Shedding of the ITIM Receptor CD31

Cited by 63 publications

References 38 publications

Ig gene-like molecule CD31 plays a nonredundant role in the regulation of T-cell immunity and tolerance

Ig gene-like molecule CD31 plays a nonredundant role in the regulation of T-cell immunity and tolerance

CD31 signals confer immune privilege to the vascular endothelium

An immunologist's guide to CD31 function in T-cells

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