Natural Killer Cells and Liver Transplantation: Orchestrators of Rejection or Tolerance?

Natural killer (NK) cells are highly heterogeneous innate lymphocytes with a diverse repertoire of phenotypes and functions. Their role in organ transplantation has been poorly defined due to conflicting clinical and experimental data. There is evidence that NK cells can contribute to graft rejection and also to tolerance induction. In most solid organ transplantation settings, the role of NK cells is only considered from the perspective of the recipient immune system. In contrast to other organs, the liver contains major resident populations of immune cells, particularly enriched with innate lymphocytes such as NK cells, NKT cells, and gamma-delta T cells. Liver transplantation therefore results in a unique meeting of donor and recipient immune systems. The unusual immune repertoire and tolerogenic environment of the liver may explain why this potentially inflammatory meeting often results in attenuated immune responses and reduced requirement for immunosuppression. Recent trials of immunosuppression withdrawal in liver transplant patients have identified NK cell features as possible predictors of tolerance. Here we propose that hepatic NK cells play a key role in the induction of tolerance post-liver transplant and examine potential mechanisms by which these cells influence liver transplant outcome.