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Curr Opin Endocrinol Diabetes Obes. 2019 Aug;26(4):213-218. doi: 10.1097/MED.0000000000000488.

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

Author information

1
Systems Immunology Program.
2
Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.

Abstract

PURPOSE OF REVIEW:

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.

RECENT FINDINGS:

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

SUMMARY:

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.

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