Faculty of 1000 evaluation for Unique autoreactive T cells recognize insulin peptides generated within the islets of Langerhans in autoimmune diabetes (original) (raw)

2010, F1000 - Post-publication peer review of the biomedical literature

Besides the genetic framework, there are two critical requirements for the development of tissuespecific autoimmune diseases. First, autoreactive T cells need to escape thymic negative selection. Second, they need to find suitable conditions for autoantigen presentation and activation in the target tissue. We show here that these two conditions are fulfilled in diabetic NOD mice. A set of autoreactive CD4 + T cells specific for an insulin peptide, with the noteworthy feature of not recognizing the insulin protein when processed by the antigen presenting cells (APC) escape thymic control, participate in diabetes and can cause disease. We also find that APCs situated in close contact with the beta cells in the islets of Langerhans bear vesicles with the antigenic insulin peptides and activate the peptide-specific T cells. These findings may be relevant for other cases of endocrine autoimmunity. Although autoimmune diabetic NOD mice exhibit a wide range of autoreactivities 1 , the one directed against the insulin molecule is prominent 2. T cells reactive to insulin were identified in NOD mice and shown to transfer diabetes into non-diabetic mice 3-7. T cells from T cell receptor (TCR) transgenic mice specific for insulin were also diabetogenic 8. Additional findings point to insulin as an important primary autoantigen for disease initiation. The amplitude of insulin expression in the thymus was linked to diabetes incidence 9-12 , and high expression of insulin in APCs using a transgene ablated diabetes development 13 , 14. Moreover, mice expressing a mutant insulin gene product not recognized by T cells did not develop diabetes 7. It is noteworthy that the T cell response to the insulin molecule is highly focused on a segment of the β-chain, encompassing residues 9-23 (B: 9-23) 15-18. This peptide binds poorly (μM affinity and has a high dissociation rate) to the class II major histocompatibility complex (MHC) molecule I-A g7 (ref 18 , 19). How a small protein that yields a very weak binding peptide and circulates at ηM concentrations can function as a significant autoantigen is surprising, and raises a number of important Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: