Natural killer cells in rejection and tolerance of solid organ allografts

Abstract

Purpose of review A series of recent papers defy conventional wisdom by showing that NK cells exert a powerful and long lasting influence on the immune response to whole organ allografts. The early activation of NK cells following transplantation is associated with killing of allogeneic target cells and release of immunomodulatory chemokines and cytokines, which can contribute to either rejection or tolerance. Here, we review findings describing NK cell receptors, potential mediators and mechanisms underlying the dual influence of NK cells in solid organ transplantation. Findings New studies show that NK cells can discriminate between self and foreign tissues and play a key role in the initiation and regulation of adaptive immune responses after solid organ transplantation. Depending upon the types of NK cell receptors engaged and the nature of cytokines released, early NK cell activation can promote either acute rejection or tolerance. Summary Solid organ transplantation is associated with the early activation of NK cells, which are then licensed to kill allogeneic target cells directly or via ADCC and release various chemokines and immunomodulatory cytokines. Depending upon the nature of NK cell subsets activated and their ability to kill allogeneic target cells and release certain types of cytokines, NK cells can promote the activation/expansion of pro-inflammatory Th1 cells or regulatory Th2/Treg cells thus tilting the balance of alloimmunity towards rejection or tolerance. An in-depth understanding of these mechanisms will be necessary in order to design therapies targeting NK cells in human transplantation.

A TLR9 agonist promotes IL-22-dependent pancreatic islet allograft survival in type 1 diabetic mice

“…Islet allografts survive for longer-terms in CD1-deficient recipient mice, which do not possess NKT cells18. In contrast to these findings, studies have suggested that NK1.1 cells promote allograft survival by APCs and by secreting IL-10, thereby promoting the response of T-regulatory cells1735. In the current study we found that depletion of NK1.1 cells during islet transplantation induced early allograft rejection, which suggests that liver NK1.1 cells induce tolerance to islet allografts.…”

NK cells are biologic and biochemical targets of 6-mercaptopurine in Crohn's disease patients

“…Key to these roles is the NK cells’ receptor repertoire for detection of surface molecules specific to microbial agents or categorically induced by the molecular stress response shared by viral infection and neoplastic states [2,5,6]. Modern studies in NK cell biology have increasingly highlighted that NK cells influence the pathophysiologic processes underlying diverse chronic inflammatory conditions such as transplant rejection [7,8], rheumatoid arthritis [9], diabetes [10], and inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn’s disease (CD) [11–15]. The mechanisms by which NK cells affect these inflammatory processes are incompletely understood, but may include direct tissue damage via parenchymal cell cytolysis and production of cytokines inducing T cell or myeloid cell recruitment and activation [16–18].…”

Maintaining T cell tolerance of alloantigens: Lessons from animal studies

“…In another study by X. Li’s group, NK cells were found to maintain transplant tolerance by killing donor APCs (186). These studies suggest that NK cells, like DCs and T cells, have dual roles in transplantation, either promoting tolerance or rejection, depending on the organ/tissue transplanted and the inflammatory milieu surrounding the allograft at the time of transplantation (187–190). …”