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

Abstract

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...

CD31 signals confer immune privilege to the vascular endothelium

“…As shown in Fig. 1 D and E, HY-specific CTL-mediated killing was significantly increased in CD31-deficient male-derived ECs, indicating that CD31 expression can protect ECs from CTL-mediated cytolysis, in line with our previous observations with CD31-expressing antigenpresenting cells (23). In addition, overall cell death, as measured by TpB exclusion, was not quantitatively different from apoptosis, as measured by TUNEL, suggesting that the latter mechanism is dominant in CTL-mediated killing of ECs.…”

“…This mechanism also is supported by the observation that the anti-CD31 antibody, which has been shown to prevent cis interactions by CD31 (32), inhibited CD31-mediated prosurvival activity induced in response to TNF-α. Activation of CD31 signaling by CTLs is likely to be induced by distinct mechanisms: first, CTLs' interaction with EC might lead to trans-CD31 ligation (23). Alternatively, CD31 might be activated indirectly by MHC ligation by the T-cell receptor (33).…”

“…We previously have reported that CD31 reduces cytotoxic killing of antigen-presenting cells (23). Selective expression of CD31 by endothelium and dendritic cells may serve the purpose of preserving their integrity and function during immune inflammation; thus, the endothelium can mediate the development of inflammatory infiltrates without being damaged by migrating activated leukocytes, and antigen-presenting dendritic cells can serially activate multiple cognate T cells without themselves being killed at the first encounter.…”

“…4 C and D) enhanced their sensitivity to TNF-α-induced apoptosis, and this enhanced sensitivity could not be rescued by CD31 antibody stimulation ( Fig. 4E) (23).…”

“…We recently have shown that in T cells CD31-mediated protection from activation-induced cell death, which is largely Fasdependent, is associated with Erk 1 and 2 but not NFκB activation (23). We therefore sought to assess whether the Erk/Akt pathway was induced in our system.…”