Abstract
Rejection of solid organ grafts is regarded to be dependent on T cell responses. Nonetheless, numerous studies have focused on the contribution of NK cells in this process, resulting in contradictory theories. While some conclude that there is no participation of NK cells, others found an inflammatory or regulative role of NK cells. However, the experimental settings are rarely comparable with regard to challenged species, strain combinations or the nature of the graft. Thus, clear definition of NK cell contribution might be impeded by these circumstances. In this study we performed heterotopic heart transplantation (HTx) in rats, choosing one donor-recipient-combination leading to a fast and a second leading to a prolonged course of graft rejection. We intervened in the rejection process, by depletion of recipient NK cells on the one hand and by injection of activated NK cells syngeneic to the recipients on the other. The fast course of rejection could not be influenced by any of the NK cell manipulative treatments. However, the more prolonged course of rejection was highly susceptible to depletion of NK cells, resulting in significant acceleration of rejection, while injection of NK cells induced acceptance of the grafts. We suggest that, depending on the specific setting, NK cells can attenuate the first trigger of immune response, which allows establishing the regulatory activity leading to tolerance of the graft.
Highlights
The participation of NK cells in rejection of solid organ grafts was first described in the early 1980s, with evidence of influx of NK cells, described as large granular lymphocytes (LGL) into rat renal allografts [1]
We included a fast rejecting donor-recipient combination and a combination of strains resulting in a prolonged rejection, to analyze the regulatory capacity of NK cells, depending on the severity of the immune response
We detected a significant increase of NK cell influx and a decrease of macrophages in the composition of infiltrating cells, whereas T cells revealed a slight increase compared to untreated rats (S5B and S5C Fig)
Summary
The participation of NK cells in rejection of solid organ grafts was first described in the early 1980s, with evidence of influx of NK cells, described as large granular lymphocytes (LGL) into rat renal allografts [1]. A study by Shelton et al reported of non-rejection of allogeneic skin-grafts in SCID mice, whereas rejection was re-established by transfer of–predominantly CD4+–T cells. NK cells in rejection of allogeneic grafts in rats [3], prompting the conclusion that the adaptive immune system plays the major role in the rejection process towards foreign tissue. It is a common consent that an effective and in best case specific prevention of graft rejection needs to abrogate the onset of an allogen-reactive T cell response. NK cells are often considered as a rather negligible if not redundant cell population in this process [4,5]
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