| The current strategy of immunosuppression in clinical transplantation does not achieve the goal of indefinite survival and a steady state of tolerance. We have chosen to analyze two models of therapy that produce a state of tolerance in animals that is the overall goal for clinical transplantation. Understanding these pathways and mechanisms of successful tolerance inducing protocols will help to gather insight for proper targets for future therapies to promote tolerance and replace the general immunosuppression approach currently exercised in clinical transplantation.; We demonstrate that allograft tolerance requires an intact host MHC class I pathway and that tolerance---or even prolonged graft survival---is completely abolished in the absence of host MHC class I. However, we found that tolerance did not require CD1d-restricted NKT cells, strongly implicating NK cells in this process. As such, results implicate a novel and dramatic requirement for host NK cells in allograft tolerance induction. Together these implications support the idea that NK cells promote tolerance not by direct interaction with donor cells, but by modulating responses of host immune cells.; In summary, results demonstrate a novel and critical role for NK cells for the induction of allograft tolerance. This finding has important pragmatic implications. For example, while NK cell reactivity is often implicated with pro-inflammatory immunity and bone marrow rejection, it may be essential to avoid NK cell inhibition in order to facilitate tolerance induction to other types of allografts. That is, a relative 'sparing' of NK cell reactivity may be an important feature of effective tolerance-promoting strategies for tissue and organ transplants. Thus, in addition to the surveillance of tumors and virus-infected cells, NK cells can also scrutinize the generation and nature of the adaptive immune response. Importantly, this activity includes the unexpectedly pivotal role in allograft tolerance induction found in these studies. It will be intriguing to determine whether NK cells comprise a component of innate immunity involved in general peripheral tolerance. |
