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

TY - JOUR

T1 - The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen

AU - Wagle, Mayura V.

AU - Marchingo, Julia M.

AU - Howitt, Jason

AU - Tan, Seong Seng

AU - Goodnow, Christopher C.

AU - Parish, Ian A.

PY - 2018/7/17

Y1 - 2018/7/17

N2 - 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.

AB - 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.

KW - anergy

KW - autoimmunity

KW - checkpoint

KW - Ndfip1

KW - peripheral tolerance

KW - T cell

KW - ubiquitin ligases

UR - https://www.scopus.com/pages/publications/85049787399

U2 - 10.1016/j.celrep.2018.06.060

DO - 10.1016/j.celrep.2018.06.060

M3 - Article

C2 - 30021156

AN - SCOPUS:85049787399

SN - 2211-1247

VL - 24

SP - 577

EP - 584

JO - Cell Reports

JF - Cell Reports

IS - 3

ER -