Journal article
The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8 T Cell Tolerance Checkpoint to High-Dose Antigen
MV Wagle, JM Marchingo, J Howitt, SS Tan, CC Goodnow, IA Parish
Cell Reports | CELL PRESS | Published : 2018
Abstract
Escape from peripheral tolerance checkpoints that control cytotoxic CD8+ T cells is important for cancer immunotherapy and autoimmunity, but pathways enforcing these checkpoints are mostly uncharted. We reveal that the HECT-type ubiquitin ligase activator, NDFIP1, enforces a cell-intrinsic CD8+ T cell checkpoint that desensitizes TCR signaling during in vivo exposure to high antigen levels. Ndfip1-deficient OT-I CD8+ T cells responding to high exogenous tolerogenic antigen doses that normally induce anergy aberrantly expanded and differentiated into effector cells that could precipitate autoimmune diabetes in RIP-OVAhi mice. In contrast, NDFIP1 was dispensable for peripheral deletion to low-..
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Awarded by National Institutes of Health
Funding Acknowledgements
We thank Debbie Howard and Sarp Kaya for technical assistance. This work was funded by NIH grant U19-AI100627, by an Australian Government Research Training Program Domestic Scholarship (to M.V.W.), by a Sydney Parker Smith Postdoctoral Research Fellowship from the Cancer Council of Victoria (to J.M.M.), and by the National Health and Medical Research Council (NHMRC) through Program Grants 1016953, 1113904, and 1054925, Australia Fellowship 585490 (to C.C.G.), Senior Principal Research Fellowship 1081858 (to C.C.G.), CJ Martin Early Career Fellowship 585518 (to I.A.P.), and Independent Research Institutes Infrastructure Support Scheme Grant 361646. Florey Institute of Neuroscience and Mental Health and WEHI acknowledge the strong support from the Victorian Government and in particular funding from the Operational Infrastructure Support Grant.