Hybrid-insulin peptides are key clinically-relevant target of T cells
by Adam Burrack, PhD
We return to two familiar topics in our series: the ground-breaking research of Katie Haskins and Thomas Delong at the University of Colorado Immunology Department and clinical samples available through the St Vincent Institute in Melbourne, Australia. For many years – perhaps since Katie Haskins’ discovery of the BDC T cell lines in the late 1980s – the Barbara Davis Center in Denver, Colorado, has been the place to study the pathogenesis of type 1 diabetes in the United States. The St Vincent’s Institute is the place to study type 1 diabetes in Australia. In this series we have profiled the work of Helen Thomas and Thomas Kay who study the biology of autoreactive T cells and how they promote beta cell death in mouse models of type 1 diabetes.
In a recent article in the journal Science, Dr Haskins, Dr Delong, and Dr Stuart Mannering from SVI report that T cells isolated from the pancreas of a human subject responded to hybrid peptides composed of a chunk from proinsulin and a chunk of another peptide. This is different from a recent report by John Kappler and colleagues, which showed a different 4-peptide sequence filling the remainder of the peptide-binding groove for the WE14 mimotope of the Chromogranin A peptide. In English, these two reports describe two different ways (composite peptides of two different targeted proteins, or ‘random filling of the binding groove’) to get to the same outcome: a T cell response directed against a known target leading to beta cell destruction.
Since the composite peptide is a “smash-up” of two different peptides, these composite peptides are “new targets” as far as the T cells are concerned. Since they are new targets, and are associated with inflammation and dead-and-dying cells, these peptides promote a T cell response. As we know, that T cell response is quite effective at destroying its target – the beta cells. Dr Haskins and colleagues go on to show accumulation of hybrid-peptide-binding T cells in the pancreas of diabetic NOD mice, as well as – here is why this paper is in Science – T cells derived from a type 1 diabetic patient also binding a (different) hybrid peptide. These data establish a new paradigm: T cells associated with development of autoimmunity can be specific for portions of two different peptides loaded into the MHC molecule. Importantly, known targets comprised both portions of the composite peptide in the mouse studies.
This discovery open the door to track and therapeutically target this new category of T cell responses. An intriguing possibility, which the authors state at the conclusion of this article, is that this category of T cell response to composite peptides is the trigger for autoimmunity in general. Preventing the formation of these composite peptides in the insulin secretory granule and/or preventing presentation of these composite peptides to T cells by antigen-presenting cells now becomes a high-tier goal for basic researchers. A final possibility are attempts to induce immunological tolerance to these composite peptides. The point is this: we may have learned what the initial targets are which seed autoimmunity. This is a “big deal” to the field, and another giant feather-in-the-cap for Dr Haskins and Dr Delong, as well as for Dr Mannering.
The press release from St Vincent’s Institute describing this new study in Science is available here.