New Publication: Partial Exhaustion of CD8 T Cells in Responders to Anti-CD3 Treatment in New-Onset Type 1 Diabetes

Study results suggesting that T cell exhaustion markers may be correlated with treatment response in type 1 diabetes (T1D) patients from the Immune Tolerance Network’s AbATE study were published today in Science Immunology. This research, led by Alice Long, PhD, and Peter Linsley, PhD, at Benaroya Research Institute, used integrated systems biology and flow cytometry approaches to investigate pathways associated with C-peptide stabilization in responders to anti-CD3 treatment. The authors determined that a population of CD8 T cells that resemble exhausted T cells is associated with the best treatment outcome, suggesting T cell exhaustion as a potential target for therapy in T1D.

AbATE was a phase II clinical study in which two doses of anti-CD3 monocolonal antibody, teplizumab, were given one year apart to individuals with new-onset type 1 diabetes. After 2 years, the anti-CD3-treated group showed significantly greater preservation of C-peptide compared to the control group (75% higher responses compared to control). Post-hoc analysis identified two groups of subjects in the treated group: “responders” who showed very little C-peptide decline over the course of the study and “non-responders” who exhibited a similar rate of C-peptide decline as the control group.

Using blood samples from AbATE responders, researchers identified a population of CD8 T cells (killer T cells) that phenotypically resemble exhausted T cells. Because T cells play a role in the loss of beta cells and progression of T1D, pathways that induce T cell exhaustion (i.e., loss of T cell function) could be effective targets for T1D interventions. The exhausted-like cells found in AbATE responders expanded following anti-CD3 treatment with levels peaking after 3-6 months. These cells express high levels of the transcription factor EOMES, effector molecules, and multiple inhibitory receptors (IRs), including TIGIT and KLRG1. In addition, the exhaustion-like gene signature correlates with C-peptide levels. These findings suggest that pathways regulating T cell exhaustion could play an important role in identifying successful immune interventions that will halt the progression of T1D.

Additional information about the AbATE clinical study including datasets, specimens and previous publications is available on ITN TrialShare.