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

Summary 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-OVA hi 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.