title: TOX2 regulates human natural killer cell development by controlling T-BET expression.
abstract: Thymocyte selection-associated high mobility group box protein family member 2 (TOX2) is a transcription factor belonging to the TOX family that shares a highly conserved high mobility group DNA-binding domain with the other TOX members. Although TOX1 has been shown to be an essential regulator of T-cell and natural killer (NK) cell differentiation in mice, little is known about the roles of the other TOX family members in lymphocyte development, particularly in humans. In this study, we found that TOX2 was preferentially expressed in mature human NK cells (mNK) and was upregulated during in vitro differentiation of NK cells from human umbilical cord blood (UCB)-derived CD34(+) cells. Gene silencing of TOX2 intrinsically hindered the transition between early developmental stages of NK cells, whereas overexpression of TOX2 enhanced the development of mNK cells from UCB CD34(+) cells. We subsequently found that TOX2 was independent of ETS-1 but could directly upregulate the transcription of TBX21 (encoding T-BET). Overexpression of T-BET rescued the TOX2 knockdown phenotypes. Given the essential function of T-BET in NK cell differentiation, TOX2 therefore plays a crucial role in controlling normal NK cell development by acting upstream of TBX21 transcriptional regulation.
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Queenie P
authors.initials: QP
authors.lastname: Vong
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Wai-Hang
authors.initials: WH
authors.lastname: Leung
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Jim
authors.initials: J
authors.lastname: Houston
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Barbara
authors.initials: B
authors.lastname: Rooney
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Martha
authors.initials: M
authors.lastname: Holladay
authors.affiliation: Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany; and.
authors.forename: Robert A J
authors.initials: RA
authors.lastname: Oostendorp
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN; Department of Pediatrics, University of Tennessee, Memphis, TN.
authors.forename: Wing
authors.initials: W
authors.lastname: Leung
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002454:Cell Differentiation; D005312:Fetal Blood / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D057809:HEK293 Cells; D024002:HMGB Proteins / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology*; D016086:Lentivirus / Q000378:metabolism; D008099:Liver / Q000196:embryology; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D016688:Mice, Inbred NOD; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020825:T-Box Domain Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D000098815:T-bet Transcription Factor
chemical_list: D018952:Antigens, CD34; D024002:HMGB Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C574439:Tox2 protein, human