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

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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-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
Volume24
Issue number3
DOIs
Publication statusPublished - 17 Jul 2018

Fingerprint

T-cells
Ligases
Ubiquitin
T-Lymphocytes
Antigens
Peripheral Tolerance
Lymphocytic choriomeningitis virus
Listeria
Medical problems
Infection
Autoimmunity
Type 1 Diabetes Mellitus
Islets of Langerhans
Immunotherapy
Precipitates
Cell Differentiation

Keywords

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

Cite this

Wagle, Mayura V. ; Marchingo, Julia M. ; Howitt, Jason ; Tan, Seong Seng ; Goodnow, Christopher C. ; Parish, Ian A. / The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen. In: Cell Reports. 2018 ; Vol. 24, No. 3. pp. 577-584.
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The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen. / Wagle, Mayura V.; Marchingo, Julia M.; Howitt, Jason; Tan, Seong Seng; Goodnow, Christopher C.; Parish, Ian A.

In: Cell Reports, Vol. 24, No. 3, 17.07.2018, p. 577-584.

Research output: Contribution to journalArticle

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