Soothing touch of CD31 protects endothelium during cellular immune responses.

CD31 is a member of the Ig gene superfamily that is present on the surface of platelets and all leukocytes (1). CD31 is also highly expressed on endothelial cells, where it represents a major constituent of the intercellular junction (1). Based on this cellular distribution and similarities in the cDNA sequence coding for extracellular domains, CD31 has initially been considered as a member “among others” of the large family of cell adhesion molecules (1). A striking illustration of this lies in the first name that the molecule was given: platelet endothelial cell adhesion molecule-1 (PECAM-1). However, the demonstration that the CD31 cytoplasmic tail contains consensus sequences typical of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) has led to a reconsideration of CD31 biological functions (1). ITIM indeed contains tyrosine residues, the phosphorylation of which creates specific docking sites for Src-homology 2 domain-containing intracellular protein-tyrosine phosphatases. These catalytic enzymes, once localized to their cytoplasmic anchors and activated, are then able to inhibit tyrosine kinase-mediated signaling, and thus cellular activation (1). Building on these data, Cheung et al. (2) present in PNAS another advance in the understanding of the regulatory roles of CD31. Their study demonstrates that CD31 signaling through ITIM is necessary to prevent inflammatory-induced endothelial cell death. Maintenance of vascular integrity during effector immune responses is a major challenge in the cooperation between the immune and the vascular systems. Endothelial cells are indeed essential to prevent the activation of the coagulation cascade, which would result in ischemic necrosis of the tissue. However, immune effectors that are activated in secondary lymphoid organs must interact with the endothelium to transit out of the bloodstream and access the antigen-rich sites, where the immune response is needed. Constitutive resistance of endothelial cells to cell death induced by inflammatory insults is therefore critical for “healthy” immune responses. This “immune privilege” of endothelial cells is well illustrated in transplantation. Because the donor is from the same species but genetically different, the recipient’s adaptive immune system recognizes donor-specific alloantigens expressed by the graft. Immune response that develops against alloantigens leads in turn to Fig. 1. T-cell– and antibody-mediated rejection of kidney allograft. (A) Typical features of T-cell–mediated rejection include infiltration of graft interstitium by recipient’s mononuclear cells, which attack donor’s tubular epithelial cells (black arrows). Despite the fact that trafficking of recipient’s mononuclear cells into the interstitium require interactions with graft endothelial cells, the latter remain unharmed both in the macrovessels and the microvessels. (B) Pattern of expression of CD31 in a kidney allograft undergoing T-cell–mediated rejection. CD31 is detected on recipient’s mononuclear cells, and donor’s endothelial cells, from both the microvessels and the macrovessels. (C ) Typical features of vascular chronic antibody-mediated rejection, also known as “graft arteriosclerosis.” Black arrow shows the thickness of the neointima. (D) The binding of alloantibodies to graft endothelial cells triggers classical complement pathway, which results in C4d deposition in graft microvessels and macrovessels. (Scale bar: 100 μm.) Abbreviations: a, artery; g, glomeruli; ptc, peritubular capillaries; t, tubules. Author contributions: O.T. wrote the paper.