Characterization of IFNγ-producing natural killer cells induced by cytomegalovirus reactivation after haploidentical hematopoietic stem cell transplantation

// Fengyan Jin 1 , Hai Lin 1 , Sujun Gao 1 , Hengxiang Wang 2 , Hongmin Yan 2 , Jinglong Guo 3 , Zheng Hu 3 , Chunhui Jin 3 , Yongqi Wang 2 , Zhidong Wang 2 , Yangzhi Zhao 1 , Yu Liu 1 , Xiaoli Zheng 2 , Yehui Tan 1 , Wei Li 1 , Yun Dai 1,3 and Yanping Yang 1 1 Department of Hematology, Cancer Center, the First Bethune Hospital of Jilin University, Changchun, Jilin, China 2 Department of Hematology, Air Force General Hospital, the Chinese People’s Liberation Army, Beijing, China 3 Institute of Translational Medicine, the First Bethune Hospital of Jilin University, Changchun, Jilin, China Correspondence to: Yun Dai, email: // Yanping Yang, email: // Keywords : NK cells, NKG2C, KIR, IFNγ, cytomegalovirus, Pathology Section Received : April 11, 2015 Accepted : December 02, 2016 Published : December 12, 2016 Abstract During human cytomegalovirus (CMV) infection after umbilical cord blood or HLA-matched hematopoietic stem cell transplantation (HSCT), a population of NKG2C-expressing natural killer (NK) cells expand and persist. The expanded NK cells express high levels of inhibitory killer immunoglobulin-like receptors (KIR) specific for self-HLA and potently produce IFNγ. However, it remains unknown whether similar events would occur after haploidentical HSCT (haplo-HSCT). Here, we demonstrated that IFNγ-producing NK cells were expanded in haplo-HSCT patients with CMV reactivation. We then identified these expanded cells as a subset of CD56 dim NK cells that expressed higher levels of both NKG2C and KIR, but lower level of NKG2A. Functionally, the subset of NK cells expressing NKG2C and self-KIR in patients with CMV reactivation accounted for IFNγ production in response to K562 cells. However, these phenomena were not observed in patients without CMV reactivation. We therefore characterized a subset of NK cells with the CD56 dim , NKG2C + , and self-KIR + phenotype that expanded and were responsible for IFNγ production during CMV infection after haplo-HSCT. Together, these findings support a notion that CMV reactivation induces expansion of more mature NK cells with memory-like features, which contributes to long-term control of both CMV infection and leukemia relapse after haplo-HSCT.