title: AKT hyperactivation confers a Th1 phenotype in thymic Treg cells deficient in TGF-β receptor II signaling.
abstract: The generation of CD4⁺Foxp3⁺ Treg cells in the thymus is crucial for immune homeostasis and self-tolerance. Recent studies have shown Treg-cell plasticity when Th-related transcriptional factors and cytokines are present. However, the mechanisms that maintain the stability of Treg cells are poorly understood. Here, using mice with a T-cell-specific deletion of the transforming growth factor-β receptor 2 (Tgfbr2⁻/⁻ mice), we identify the restriction of AKT activation as a key event for the control of Treg-cell stability in Th1 inflammation. AKT regulation was evident in thymic CD4⁺Foxp3⁺ Treg cells before they egressed to peripheral tissues. CD4⁺Foxp3⁺ thymocytes from mice with the Tgfbr2 deletion expressed high levels of CXCR3 and T-bet, and produced IFN-γ and TNF-α. Thymic Tgfbr2⁻/⁻ Treg cells also showed an increase in the activation of AKT pathway. Enhanced AKT activity induced the expression of IFN-γ both in natural and inducible Treg cells. Inhibition of AKT activity markedly attenuated the expression of IFN-γ and TNF-α in thymic Tgfbr2⁻/⁻ Treg cells in vivo. In addition, mixed bone marrow transplantation showed that TGF-β signaling maintained Treg-cell stability in an intrinsic manner. Our results demonstrate that AKT hyperactivation contributes to the conversion of Treg cells to a Th1 phenotype.
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.forename: Yingqian
authors.initials: Y
authors.lastname: Xu
authors.forename: Jiabin
authors.initials: J
authors.lastname: Sun
authors.forename: Aihui
authors.initials: A
authors.lastname: Ma
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Suhua
authors.initials: S
authors.lastname: Xia
authors.forename: Guiqin
authors.initials: G
authors.lastname: Xu
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D010766:Phosphorylation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D018417:Th1 Cells / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: AKT; Stability; TGF-β; Thymus; Treg cells