title: The E3 ubiquitin ligase GRAIL regulates T cell tolerance and regulatory T cell function by mediating T cell receptor-CD3 degradation.
abstract: T cell activation is tightly regulated to avoid autoimmunity. Gene related to anergy in lymphocytes (GRAIL, encoded by Rnf128) is an E3 ubiquitin ligase associated with T cell tolerance. Here, we generated and analyzed GRAIL-deficient mice and found they were resistant to immune tolerance induction and exhibited greater susceptibility to autoimmune diseases than wild-type mice. GRAIL-deficient naive T cells, after activation, exhibited increased proliferation and cytokine expression than controls and did not depend on costimulation for effector generation. Moreover, GRAIL-deficient regulatory T (Treg) cells displayed reduced suppressive function, associated with increased Th17 cell-related gene expression. GRAIL-deficient naive and Treg cells were less efficient in downregulating T cell receptor (TCR)-CD3 expression after activation and exhibited increased NFATc1 transcription factor expression; GRAIL expression promoted CD3 ubiquitinylation. Our results indicate that GRAIL, by mediating TCR-CD3 degradation, regulates naive T cell tolerance induction and Treg cell function.
authors.affiliation: Department of Immunology, M.D. Anderson Cancer Center, Houston, TX 77030, USA. rnurieva@mdanderson.org
authors.forename: Roza I
authors.initials: RI
authors.lastname: Nurieva
authors.forename: Shuling
authors.initials: S
authors.lastname: Zheng
authors.forename: Wei
authors.initials: W
authors.lastname: Jin
authors.forename: Yeonseok
authors.initials: Y
authors.lastname: Chung
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Gustavo J
authors.initials: GJ
authors.lastname: Martinez
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Reynolds
authors.forename: Sung-Ling
authors.initials: SL
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.forename: Shao-Cong
authors.initials: SC
authors.lastname: Sun
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000276:immunology*; D005786:Gene Expression Regulation; D007108:Immune Tolerance / Q000276:immunology*; D015151:Immunoblotting; D051379:Mice; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology*
chemical_list: D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; C520250:RNF128 protein, human; D044767:Ubiquitin-Protein Ligases