The E3 ubiquitin ligase GRAIL regulates T cell tolerance and regulatory T cell function by mediating T cell receptor-CD3 degradation.
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.
Nurieva
Roza I
RI
Department of Immunology, M.D. Anderson Cancer Center, Houston, TX 77030, USA. rnurieva@mdanderson.org
Zheng
Shuling
S
Jin
Wei
W
Chung
Yeonseok
Y
Zhang
Yongliang
Y
Martinez
Gustavo J
GJ
Reynolds
Joseph M
JM
Wang
Sung-Ling
SL
Lin
Xin
X
Sun
Shao-Cong
SC
Lozano
Guillermina
G
Dong
Chen
C
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*
D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; C520250:RNF128 protein, human; D044767:Ubiquitin-Protein Ligases