Enumerating autoreactive T cells in peripheral blood: a big step in diabetes prediction

In this issue of the JCI, Trudeau and colleagues make a bold statement: “We show, we believe for the first time, that the development of an autoimmune disease can be predicted based on the presence of antigen-specific cytotoxic T cells in the peripheral blood.” (1). We suspect that, like most “firsts,” this one will be challenged. Nevertheless, based on recent workshops showing the difficulty analyzing autoreactive T cells in patients with type 1 diabetes and in animal models of this disease (2, 3), these commentators are inclined to accept this very important “first.” Though type 1 diabetes is marked by pancreatic islet β cell–specific autoantibodies and can be predicted with highly specific and sensitive autoantibody assays (4, 5), β cell damage and destruction are mediated by T cells (both CD4+ and CD8+) (5, 6). Thus, quantifying islet-reactive T cells in patients genetically at high risk to develop disease and in patients with prediabetes may be a more direct (and at least complementary) approach to detect β cell autoimmunity and predict which patients will go on to develop disease. In type 1 diabetes, assays must be able to identify autoreactive cells in the peripheral blood, not just the target organ and surrounding lymphoid tissue where they accumulate, since the blood is the only place where sampling can be routinely done. However, the hurdles have been so high and progress so limited, it has been debated whether autoreactive T cells circulate in sufficient quantities to be directly detected. Assays that quantify and characterize the function of islet-specific T cells in blood are also needed to monitor therapeutic trials in type 1 diabetes. To date, two very large trials of therapies to prevent type 1 diabetes have failed to show an effect on an apparently inexorable disease progression (7). Although one of the therapies was directed at insulin-specific T cells, no reliable assays monitored effects on this cell population. The efforts have been compared to testing therapies that prevent hypertensive kidney disease without being able to measure blood pressure.