title: PP6 controls T cell development and homeostasis by negatively regulating distal TCR signaling.
abstract: T cell development and homeostasis are both regulated by TCR signals. Protein phosphorylation and dephosphorylation, which are catalyzed by protein kinases and phosphatases, respectively, serve as important switches controlling multiple downstream pathways triggered by TCR recognition of Ags. It has been well documented that protein tyrosine phosphatases are involved in negative regulation of proximal TCR signaling. However, how TCR signals are terminated or attenuated in the distal TCR signaling pathways is largely unknown. We investigated the function of Ser/Thr protein phosphatase (PP) 6 in TCR signaling. T cell lineage-specific ablation of PP6 in mice resulted in enhanced thymic positive and negative selection, and preferential expansion of fetal-derived, IL-17-producing Vγ6Vδ1(+) T cells. Both PP6-deficient peripheral CD4(+) helper and CD8(+) cytolytic cells could not maintain a naive state and became fast-proliferating and short-lived effector cells. PP6 deficiency led to profound hyperactivation of multiple distal TCR signaling molecules, including MAPKs, AKT, and NF-κB. Our studies demonstrate that PP6 acts as a critical negative regulator, not only controlling both αβ and γδ lineage development, but also maintaining naive T cell homeostasis by preventing their premature activation before Ag stimulation.
authors.affiliation: State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, National Center for International Research of Development and Disease, School of Life Sciences, Fudan University, Shanghai 200433, China;
authors.forename: Jian
authors.initials: J
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, National Center for International Research of Development and Disease, School of Life Sciences, Fudan University, Shanghai 200433, China;
authors.forename: Hao
authors.initials: H
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, National Center for International Research of Development and Disease, School of Life Sciences, Fudan University, Shanghai 200433, China;
authors.forename: Ye
authors.initials: Y
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, National Center for International Research of Development and Disease, School of Life Sciences, Fudan University, Shanghai 200433, China;
authors.forename: Chao
authors.initials: C
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, National Center for International Research of Development and Disease, School of Life Sciences, Fudan University, Shanghai 200433, China;
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, National Center for International Research of Development and Disease, School of Life Sciences, Fudan University, Shanghai 200433, China;
authors.forename: Chenyu
authors.initials: C
authors.lastname: Li
authors.affiliation: State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, National Center for International Research of Development and Disease, School of Life Sciences, Fudan University, Shanghai 200433, China;
authors.forename: Kejing
authors.initials: K
authors.lastname: Deng
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109;
authors.forename: Jianguo
authors.initials: J
authors.lastname: Geng
authors.affiliation: State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, National Center for International Research of Development and Disease, School of Life Sciences, Fudan University, Shanghai 200433, China; Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06536;
authors.forename: Tian
authors.initials: T
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, National Center for International Research of Development and Disease, School of Life Sciences, Fudan University, Shanghai 200433, China; Department of Immunology, Duke University Medical Center, Durham, NC 27701; and.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhuang
authors.affiliation: School of Life Sciences, East China Normal University, Shanghai 200241, China wufan_tao@fudan.edu.cn bzheng@bcm.edu.
authors.forename: Biao
authors.initials: B
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, National Center for International Research of Development and Disease, School of Life Sciences, Fudan University, Shanghai 200433, China; wufan_tao@fudan.edu.cn bzheng@bcm.edu.
authors.forename: Wufan
authors.initials: W
authors.lastname: Tao
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002469:Cell Separation; D005434:Flow Cytometry; D006706:Homeostasis / Q000276:immunology*; D015151:Immunoblotting; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010749:Phosphoprotein Phosphatases / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D011948:Receptors, Antigen, T-Cell; D010749:Phosphoprotein Phosphatases; C106079:protein phosphatase 6