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

摘要

We previously reported that costimulation blockade by abatacept limits the decline of P-cell function and the frequency of circulating CD4~+ central memory T cells (T_(CM)) (CD45RO~+CD62L~+) in new-onset type 1 diabetes. In human subjects receiving placebo, we found a significant association between an increase in CD4~+ T_(CM) cells and the decline of beta-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 T_(CM) and p-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 P-cell function that is a component of the natural history of the disease. Although these data suggest immunological markers for predicting change in P-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.