Tae-Jin Kim*,1, Nayoung Kim*,1, Hyoung Jin Kang†,1, Eun-Ok Kim*, Sung Tae Kim*, Hyo Seop Ahn†, Jeffrey A. Bluestone‡ and Kyung-Mi Lee*,2
*Global Research Lab, Department of Biochemistry and Division of Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Seoul, Korea;
†Division of Hematology/Oncology, Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; and
‡University of California San Francisco Diabetes Center and Immune Tolerance Network, San Francisco, California, USA
2.Correspondence: Global Research Lab, International Center for Converging Technology, Korea University, Anam-Dong, Seongbuk-Gu, Seoul 131-701, Republic of Korea.
1. These authors contributed equally to this work.
The role of NK cells in allogeneic HCT has been increasingly appreciated, particularly in the GVL effect. Although FK506 has been used widely to prevent GVHD, its action was considered to be primarily through activated T cells. In this study, we provide direct evidence for the first time that human NK cells are immediate targets of FK506. Our in vivo data from patients undergoing peripheral blood stem cell transplantation or BMT showed a reduced number of NK cells with down-regulated CD25 expression in their peripheral blood compartment. Likewise, FK506 caused profound inhibition of NK cell proliferation in vitro and suppressed NK cytotoxicity and cytokine secretion in response to IL-2. These defects were accompanied by impaired cell clustering and selective down-regulation of adhesion molecules, ICAM-1, CD2, CD49d, and CD58. Furthermore, FK506 specifically inhibited expression of NKG2D, CD48, and DNAM1 receptors without affecting that of 2B4, NKp30, NKp44, and NKp46. As a result, natural cytotoxicity against K562 tumor targets was impaired, while leaving redirected ADCC via 2B4 intact. Finally, FK506-treated NK cells showed impaired IL-2R signaling and inhibition of STAT3. Collectively, these signaling impairments and selective down-regulation of NK receptors by FK506 may underlie the proliferative and functional defects of NK cells. Thus, our data provide a new insight into the mechanism of immunosuppression by FK506, which should be considered to interpret the outcome of graft transplantation.
tacrolimus, IL-2 receptor, STAT3, NK receptors
The online version of this manuscript, found at www.jleukbio.org, includes supplemental information.
Received March 15, 2010.
Revision received June 6, 2010.
Accepted June 21, 2010.