Extracellular vesicles in allograft rejection and tolerance

Abstract

Extracellular vesicles (EVs), including exosomes, ectosomes and apoptotic vesicles, play an essential role in communication between cells of the innate and adaptive immune systems. Recent studies showed that EVs released after transplantation of allogeneic tissues and organs are involved in the immune recognition and response leading to rejection or tolerance in mice. After skin, pancreatic islet, and solid organ transplantation, donor-derived EVs were shown to initiate direct inflammatory alloresponses by T cells leading to acute rejection. This occurred through presentation of intact allogeneic MHC molecules on recipient antigen presenting cells (MHC cross-dressing) and subsequent activation of T cells via semi-direct allorecognition. On the other hand, some studies have documented the role of EVs in maternal tolerance of fetal alloantigens during pregnancy and immune privilege associated with spontaneous tolerance of liver allografts in laboratory rodents. The precise nature of the EVs, which are involved in rejection or tolerance, and the cells which produce them, is still unclear. Nevertheless, several reports showed that EVs released in the blood and urine by allografts can be used as biomarkers of rejection. This article reviews current knowledge on the contribution of EVs in allorecognition by T cells and discusses some mechanisms underlying their influence on T cell alloimmunity in allograft rejection or tolerance.

Keywords: Allografts; Exosomes; Rejection; tolerance.

Figure 1.. MHC cross-dressing can promote interaction between helper or regulatory CD4⁺ T cells and effector T cells

Panel A shows how donor MHC class I cross-dressing of a recipient APC might promote cooperation between CD4⁺ T helper cells and CD8⁺ T effector cells by having self-MHC class II + donor peptide (indirect presentation) and donor MHC class I co-presented on the same APC (semi-direct presentation) (three cell cluster). Panel B shows how simultaneous presentation of intact donor MHC molecules (semi-direct pathway) and self-MHC class II bound to a donor peptide (indirect pathway) or a self-peptide on the same recipient APC can promote interaction between regulatory CD4⁺ Tregs and effector CD4⁺ and CD8⁺ T cells. In this scenario, it is possible that Tregs can suppress effector T cells displaying the same self-MHC class II-peptide complex as recipient APCs (T-T interaction). In this setting, effector T cells are specific for donor MHC while Tregs are not donor specific but interact with self-MHC class II-peptide complexes on activated effector T cells.