The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen

Mayura V. Wagle, Julia M. Marchingo, Jason Howitt, Seong Seng Tan, Christopher C. Goodnow, Ian A. Parish

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)
150 Downloads (Pure)


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-dose exogenous or pancreatic islet-derived antigen and had little impact upon effector responses to Listeria or acute LCMV infection. These data provide evidence that NDFIP1 mediates a CD8+ T cell tolerance checkpoint, with a different mechanism to CD4+ T cells, and indicates that CD8+ T cell deletion and anergy are molecularly separable checkpoints. Ndfip1 restrains CD4+ T cell differentiation, but its role in CD8+ T cells is unclear. Wagle et al. show that Ndfip1 selectively enforces peripheral CD8+ T cell tolerance to abundant antigen while minimally affecting both CD8+ T cell tolerance to scarce antigen and effector expansion and differentiation during acute infection.

Original languageEnglish
Pages (from-to)577-584
Number of pages8
JournalCell Reports
Issue number3
Publication statusPublished - 17 Jul 2018


  • anergy
  • autoimmunity
  • checkpoint
  • Ndfip1
  • peripheral tolerance
  • T cell
  • ubiquitin ligases

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology


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