Low-avidity self-specific T cells display a pronounced expansion defect that can be overcome by altered peptide ligands

Thymic expression of self-Ags results in the deletion of high-avidity self- specific T cells, but, at least for certain Ags, a residual population of s elf-specific T cells with low-affinity TCRs remains after negative selectio n. Such self-specific T cells are thought to play a role in the induction o f T cell-mediated autoimmunity, but may also be used for the induction of a ntitumor immunity against self-Ags. In this study, we examine the functiona l competence of a polyclonal population of self-specific CD8(+) T cells. We show that low-affinity interactions between TCR and peptide are associated with selective loss of critical T cell functions. Triggering of low levels of IFN-gamma production and cytolytic activity through low-affinity TCRs r eadily occurs provided high Ag doses are used, but IL-2 production and clon al expansion are severely reduced at all Ag doses. Remarkably, a single pep tide variant can form an improved ligand for the highly diverse population of low-avidity self-specific T cells and can improve their proliferative ca pacity. These data provide insight into the inherent limitations of self-sp ecific T cell responses through low-avidity TCR signals and the effect of m odified peptide ligands on self-specific T cell immunity.