Progression of autoimmune diabetes driven by avidity maturation of a T-cell population

Abdelaziz Amrani, Joan Verdaguer, Pau Serra, Sabrina Tafuro, Rusung Tan and Pere Santamaria ()
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Abdelaziz Amrani: Faculty of Medicine, University of Calgary, Health Sciences Centre
Joan Verdaguer: Faculty of Medicine, University of Calgary, Health Sciences Centre
Pau Serra: Faculty of Medicine, University of Calgary, Health Sciences Centre
Sabrina Tafuro: MRC Human Immunology Unit, Institute of Molecular Medicine, John Radcliffe Hospital
Rusung Tan: University of British Columbia and BC's Children's Hospital
Pere Santamaria: Faculty of Medicine, University of Calgary, Health Sciences Centre

Nature, 2000, vol. 406, issue 6797, 739-742

Abstract: Abstract For unknown reasons, autoimmune diseases such as type 1 diabetes develop after prolonged periods of inflammation of mononuclear cells in target tissues1. Here we show that progression of pancreatic islet inflammation to overt diabetes in nonobese diabetic (NOD) mice is driven by the ‘avidity maturation’ of a prevailing, pancreatic beta-cell-specific T-lymphocyte population carrying the CD8 antigen. This T-lymphocyte population recognizes two related peptides (NRP and NRP-A7)2 in the context of H-2Kd class I molecules of the major histocompatibility complex (MHC). As pre-diabetic NOD mice age, their islet-associated CD8+ T lymphocytes contain increasing numbers of NRP-A7-reactive cells, and these cells bind NRP-A7/H-2Kd tetramers with increased specificity, increased avidity and longer half-lives. Repeated treatment of pre-diabetic NOD mice with soluble NRP-A7 peptide blunts the avidity maturation of the NRP-A7-reactive CD8+ T-cell population by selectively deleting those clonotypes expressing T-cell receptors with the highest affinity and lowest dissociation rates for peptide–MHC binding. This inhibits the local production of T cells that are cytotoxic to beta cells, and halts the progression from severe insulitis to diabetes. We conclude that avidity maturation of pathogenic T-cell populations may be the key event in the progression of benign inflammation to overt disease in autoimmunity.

Date: 2000
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DOI: 10.1038/35021081

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