Introduction: In the context of kidney transplantation (KTx), little is known about the involvement of Natural Killer (NK) cells in the immune reaction leading to rejection or immunological tolerance under immunosuppression (IS). Therefore, the peripheral NK cell repertoire of patients after kidney transplantation (KTx) was investigated to identify NK cell subsets that may be associated with immunosuppression. Methods: PBMC and plasma were isolated from blood samples taken in parallel to a kidney biopsy at 3, 6 or 12 month after KTx. Detection of absolute cell numbers (n=122) and NK cell subset analysis (n=21) were performed by FACS. The presence of anti-HLA-Abs (DSA, n=122) was determined by Luminex technology. To investigate the effects of IS, IFNg-ELISpots, in vitro-degranulation and proliferation assays were performed with PBMC of healthy donors. Results: We could demonstrate that the NK cell repertoire in peripheral blood of KTx patients differs significantly from healthy individuals. The presence of DSAs was associated with reduced numbers of CD56^dim NK cells (p=0.009). Moreover, in KTx-patients, down-modulation of CD16 and CD6 on CD56^dim NK cells was observed with significant differences between CsA- and Tac-treated patients (p=0.002). Tac-treatment was associated with decreased CD69 (p=0.04), slightly decreased HLA-DR and increased CD94/NKG2A expression in CD56^dim NK cells indicating that the quality of IS treatment impinges on the peripheral NK cell repertoire. In vitro studies with PBMC of healthy donors showed that this modulation of CD16, CD6, CD69, and HLA-DR could also be induced experimentally. The presence of CNI or the mTORi sirolimus had also functional consequences regarding degranulation and IFN-g-production against K562 target cells. Conclusions: We postulate here that the NK cell composition in peripheral blood of KTx patients represents an important hallmark of the efficacy of IS and may be informative for the immune status after Tx in terms of rejection vs. drug-induced allograft tolerance.

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