Abstract
Background. Natural killer (NK) cells play a dichotomous role in alloimmune responses because they are known to promote both allograft survival and rejection. The aim of this study was to investigate the role of functionally distinct NK cell subsets in alloimmunity with the hypothesis that this dichotomy is explained by the functional heterogeneity of distinct NK cell subsets. Methods. Because ...
Abstract
Background. Natural killer (NK) cells play a dichotomous role in alloimmune responses because they are known to promote both allograft survival and rejection. The aim of this study was to investigate the role of functionally distinct NK cell subsets in alloimmunity with the hypothesis that this dichotomy is explained by the functional heterogeneity of distinct NK cell subsets. Methods. Because T-bet controls the maturation of NK cells from CD27(high) to terminally differentiated CD27(low) NK cells, we used Rag(-/-)T-bet(-/-) mice that lack mature CD27(low) NK cells to study the distinct roles of CD27(low) versus CD27(high) NK cells in a model of T cell-mediated skin transplant rejection under costimulatory blockade conditions. Results. We found that T cell-reconstituted Rag1(-/-)recipients (possessing CD27(low) NK cells) show significantly prolonged allograft survival on costimulatory blockade when compared to Rag1(-/-)T-bet(-/-) mice (lacking CD27(low) NK cells), indicating that CD27(low) but not CD27(high) NK cells enhance allograft survival. Critically, Rag1(-/-)T-bet(-/-) recipients showed strikingly increased alloreactive memory CD8(+) T cell responses, as indicated by increased CD8(+) T cell proliferation and interferon-gamma production. Therefore, we speculated that CD27(low) NK cells directly regulate alloreactive CD8(+) T cell responses under costimulatory blockade conditions. To test this, we adoptively transferred CD27(low) NK cells into Rag1(-/-)T-bet(-/-) skin transplant recipients and found that the CD27(low) NK cells restore better allograft survival by inhibiting the proliferation of alloreactive interferon-gamma(+)CD8(+) T cells. Conclusions. In summary, mature CD27(low) NK cells promote allograft survival under costimulatory blockade conditions by regulating alloreactive memory CD8(+) T-cell responses.
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