title: Expression of Twist2 is controlled by T-cell receptor signaling and determines the survival and death of thymocytes.
abstract: Self-reactive thymocytes are eliminated by negative selection, whereas competent thymocytes survive by positive selection. The strength of the T-cell receptor (TCR) signal determines the fate of thymocytes undergoing either positive or negative selection. The TCR signal strength is relatively higher in negative selection than in positive selection and induces pro-apoptotic molecules such as Nur77 and Nor-1, which are members of the orphan nuclear receptor family, that then cause TCR-mediated apoptosis. However, at the molecular level, it remains unclear how positive or negative selection is distinguished based on the TCR signal. We found that the expression of Twist2 is differentially regulated in positively and negatively selected thymocytes. In particular, TCR signal strength that elicits positive selection induces Twist2 expression via the Ca2+-Cacineurin-NFATc3 pathway, whereas strength of the TCR signal that results in negative selection abolishes NFATc3-dependent Twist2 induction via specific activation of the JNK pathway. Using Twist2-deficient and Twist2 transgenic mice, we also found that Twist2 determines thymocyte sensitivity to TCR-mediated apoptosis by regulating the expression of Nur77 and Nor-1. Twist2 partially retains histone deacetylase 7 (HDAC7) in the nucleus and recruits it to the Nur77 promoter region to repress Nur77 in positively selected thymocytes. Thus our results suggest a molecular mechanism of how thymocytes interpret the strength of the TCR signal and how TCR sensitivity is controlled during thymic selection.
authors.affiliation: School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: S
authors.initials: S
authors.lastname: Oh
authors.affiliation: School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: J
authors.initials: J
authors.lastname: Oh
authors.affiliation: School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: C
authors.initials: C
authors.lastname: Lee
authors.affiliation: School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: S
authors.initials: S
authors.lastname: Oh
authors.affiliation: School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: S
authors.initials: S
authors.lastname: Jeon
authors.affiliation: School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: J
authors.initials: J
authors.lastname: Choi
authors.affiliation: School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: S
authors.initials: S
authors.lastname: Hwang
authors.affiliation: School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Y
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Graduate School of Cancer Science and Policy, National Cancer Center, Gyeonggi 10408, Republic of Korea.
authors.forename: H
authors.initials: H
authors.lastname: Lee
authors.affiliation: School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: R H
authors.initials: RH
authors.lastname: Seong
mesh_terms: D000818:Animals; D017209:Apoptosis; D019703:Calcineurin / Q000378:metabolism; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D064326:MEF2 Transcription Factors / Q000378:metabolism; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D012097:Repressor Proteins / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D060168:Thymocytes / Q000166:cytology* / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000172:deficiency / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; C578044:Mef2d protein, mouse; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; C490411:Nr4a3 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011948:Receptors, Antigen, T-Cell; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D051879:Twist-Related Protein 1; C096852:Twist2 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D019703:Calcineurin; C543274:Hdac7 protein, mouse; D006655:Histone Deacetylases