T cells in type 1 diabetes: Instructors, regulators and effectors: A comprehensive review.

Type 1 diabetes was one of the earliest disorders to be associated with the phenomenon of autoimmunity and is one of the most studied organ-specific autoimmune diseases at the epidemiologic, immunologic and genetic level. Despite this, and the emergence of a plethora of strategies for trying to intervene in, or prevent the disease, it remains at some distance from being reliably and safely tractable by immunotherapy, a source of great frustration in this research field. In this article we review some of the key concepts that might impact upon this lack of success in the clinic going forward. These include new insights into autoreactive CD4 and CD8 T cell biology and a discussion of the concept of disease heterogeneity as it applies to type 1 diabetes. The onset of disease is characterised by a delicate equilibrium of proinflammatory and regulatory T cells, which we have termed "balanced autoreactive set-point", and which may be amenable to antigen-specific immunotherapies that alter the rate of disease progression. Advances in the characterization of T cells, especially at the single cell level, could be rewarding, notably from the vantage point of biomarker and surrogate discovery. A better understanding of T cell targeting, autoantigen processing and the β-cell:immune interface is also needed, although access to diseased tissues is a major limitation in this effort. Finally, the existence of disease heterogeneity is an emerging theme in this and other complex immunopathologies, and could be both a blessing (finding the right drug for the right person) and a hindrance (compromising the power of early-stage trials of emerging therapeutics).