The frequency of high avidity T cells determines the hierarchy of determinant spreading

Autoimmunity often spreads in a predefined pattern during the progression o f T cell-mediated autoimmune diseases. This progression has been well descr ibed in animal models and in man, but the basis for this phenomenon is litt le understood. To gain insight into the factors that determine this spreadi ng hierarchy, we characterized the binding affinity of a panel of beta cell -autoantigenic peptides to I-Ag7, as well as the precursor frequency, funct ional avidity, and phenotype of the T cells that recognize these peptides i n type 1 diabetes-prone nonobese diabetic mice. We observed that autoimmuni ty gradually spreads from a beta cell determinant, which had the largest pr ecursor pool of high avidity T cells, to beta cell determinants with progre ssively smaller and lower avidity T cell precursor pools. This correlation between the sequential development of spontaneous T cell autoimmunity and t he frequency and avidity of autoantigen-reactive T cells suggests that the extent to which T cells were negatively selected by the self-determinants i s the key factor determining the spreading hierarchy.