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

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.

Autoreactive CD8+ T cell exhaustion distinguishes subjects with slow type 1 diabetes progression

“…Individuals with T1D with slow disease progression showed enrichment for islet-specific cells with functional features of exhaustion, regardless of disease duration and after accounting for age. T cell exhaustion plays opposing roles; it is deleterious in tumor and chronic viral infection (42,57) but, as recently appreciated, beneficial in autoimmunity (58). Interestingly, we also observed the association of the exhaustion phenotype with slow disease progression among the polyclonal CD8 + T cell population within the same subjects, which suggests that intrinsic factors may promote exhaustion of islet-specific and total CD8 + T cells in slow progressors.…”

Soluble CD137 Ameliorates Acute Type 1 Diabetes by Inducing T Cell Anergy

“…These results highlight possible regulatory roles of APCs and other immune cells; clearly, several APCs express CD137L and could be affected by sCD137 treatment, which has not been explored here. Furthermore, just as on the one hand, checkpoint inhibitors can precipitate acute T1D (44), harnessing immune checkpoints to induce T cell exhaustion is another therapeutic approach (45). Although we show that sCD137 specifically targets CD8 T cells and CD8 memory subsets, we do not show whether it induces immune exhaustion in these cells, which should be explored in future studies.…”

Viral Infections and Systemic Lupus Erythematosus: New Players in an Old Story

“…A selective induction of this T cell phenotype might represent a new therapeutic tool to blunt autoimmunity, although its potentially detrimental effect on an associated chronic viral infection requires further study. Of interest is the fact that an anti-CD3+ therapy (teplizumab) to promote islet-specific CD8+ T-cell exhaustion showed a beneficial role in type 1 diabetes [ 209 ].…”