The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8(+) T Cell Tolerance Checkpoint to High-Dose Antigen
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.
|Authors||Wagle, M. V.; Marchingo, J. M.; Howitt, J.; Tan, S. S.; Goodnow, C. C.; Parish, I. A.|
|Responsible Garvan Author||Prof Christopher Goodnow|
|Publisher Name||Cell Reports|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/30021156|