Research ArticleTYPE 1 DIABETES

Partial exhaustion of CD8 T cells and clinical response to teplizumab in new-onset type 1 diabetes

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Science Immunology  18 Nov 2016:
Vol. 1, Issue 5, eaai7793
DOI: 10.1126/sciimmunol.aai7793

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Exhausting autoimmunity

Checkpoint inhibitors have revolutionized cancer immunotherapy, allowing potentially exhausted tumor-reactive T cells to attack the tumor. However, in the case of autoimmunity, exhausted T cells may be the answer to stopping the disease. Long et al. report that, in type 1 diabetics treated with the anti-CD3 monoclonal antibody teplizumab, CD8 T cells with features of exhausted T cells are associated with best response to treatment. These cells recognized a broad spectrum of autoantigens and proliferated at a lower level ex vivo, yet their exhausted phenotype was not terminal because stimulating these cells with a ligand for the inhibitory receptor TIGIT further down-regulated their activation. These data suggest inducing T cell exhaustion as a potential therapeutic approach for type 1 diabetes.

Abstract

Biologic treatment of type 1 diabetes (T1D) typically results in transient stabilization of C-peptide levels (a surrogate for endogenous insulin secretion) in some patients, followed by progression at the same rate as in untreated control groups. We used integrated systems biology and flow cytometry approaches with clinical trial blood samples to elucidate pathways associated with C-peptide stabilization in T1D patients treated with the anti-CD3 monoclonal antibody teplizumab. We identified a population of CD8 T cells that accumulated in patients with the best response to treatment (responders) and showed that these cells phenotypically resembled exhausted T cells by expressing high levels of the transcription factor EOMES, effector molecules, and multiple inhibitory receptors (IRs), including TIGIT and KLRG1. These cells expanded after treatment, with levels peaking after 3 to 6 months. To functionally characterize these exhausted-like T cells, we isolated memory CD8 TIGIT+KLRG1+ T cells from responders and showed that they exhibited expanded T cell receptor clonotypes (indicative of previous in vivo expansion), recognized a broad-based spectrum of environmental antigens and autoantigens, and were hypoproliferative during polyclonal stimulation, increasing expression of IR genes and decreasing cell cycle genes. Triggering these cells with a recombinant ligand for TIGIT during polyclonal stimulation further down-regulated their activation, demonstrating that their exhausted phenotype was not terminal. These findings identify and functionally characterize a partially exhausted cell type associated with response to teplizumab therapy and suggest that pathways regulating T cell exhaustion may play a role in successful immune interventions for T1D.

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