Costimulation Blockade Disrupts CD4+ T Cell Memory Pathways and Uncouples Their Link to Decline in β-Cell Function in Type 1 Diabetes

This is the author accepted manuscript. The final version is available from the American Association of Immunologists via the DOI in this recordData and resource availability: The datasets generated during the current study are available from the corresponding author upon reasonable request. Clinical data and patient characteristics can be requested from the National Institute of Diabetes and Digestive and Kidney Diseases public repository at https://repository.niddk.nih.gov/studies/trialnet/We previously reported that costimulation blockade by abatacept limits the decline of b-cell function and the frequency of circulating CD4+ central memory T cells (TCM) (CD45RO+CD62L+) in new-onset type 1 diabetes. In human subjects receiving placebo, we found a significant association between an increase in CD4+ TCM cells and the decline of b-cell function. To extend and refine these findings, we examined changes in human CD4+ and CD8+ naive and memory T cell subsets at greater resolution using polychromatic flow and mass cytometry. In the placebo group, we successfully reproduced the original finding of a significant association between TCM and b-cell function and extended this to other T cell subsets. Furthermore, we show that abatacept treatment significantly alters the frequencies of a majority of CD4+ conventional and regulatory T cell subsets; in general, Ag-naive subsets increase and Ag-experienced subsets decrease, whereas CD8+ T cell subsets are relatively resistant to drug effects, indicating a lesser reliance on CD28-mediated costimulation. Importantly, abatacept uncouples the relationship between changes in T cell subsets and b-cell function that is a component of the natural history of the disease. Although these data suggest immunological markers for predicting change in b-cell function in type 1 diabetes, the finding that abatacept blunts this relationship renders the biomarkers nonpredictive for this type of therapy. In sum, our findings point to a novel mechanism of action for this successful immunotherapy that may guide other disease-modifying approaches for type 1 diabetes.National Institutes of Health (NIH)National Institute for Health Research (NIHR