Enforcing the checkpoints: harnessing T-cell exhaustion for therapy of T1D

Although checkpoint inhibitor blockade is now widely used clinically for cancer immunotherapy, the reverse process, (i.e. induction of checkpoints to slow autoimmunity) has not been extensively explored. CD8 T-cell exhaustion is a state of immune hyporesponsiveness that may be harnessed to treat autoimmunity.

We focus on the potential role of CD8 T-cell exhaustion as a mechanism of peripheral tolerance in T1D and its therapeutic implications.

CD8 T-cell exhaustion is a continuum in which cells change from precursor to terminally exhausted cells. Current thinking based on studies in cancer and chronic viral infection invokes a three-signal model for development of T-cell exhaustion, with persistent antigen, negative costimulatory signals and chronic inflammation comprising signals 1-3, respectively. Transcriptional signatures of CD8 T-cell exhaustion were associated with better prognosis across several autoimmune diseases, most profoundly in systemic diseases. In T1D, CD8 exhaustion was promoted by treatment with anti-CD3 therapy (teplizumab) and was more evident in islet-specific CD8 T cells of slow progressors, suggesting a beneficial role in T1D also. Thus, we apply this three-step process of exhaustion to discuss potential treatments to augment CD8 T-cell exhaustion in T1D.