Subsets of Nonclonal Neighboring CD4+ T Cells Specifically Regulate the Frequency of Individual Antigen-Reactive T Cells

SUMMARY After an immune response, the expanded population of antigen-specific CD4 + T cells contract to steady state levels. We have found that the contraction is neither cell-autonomous nor mediated by competition for generic trophic factors, but regulated by relatively rare subsets of neighboring CD4 + T cells not necessarily of a conventional regulatory T cell lineage. These regulators, referred to as deletors, specifically limit the frequency of particular antigenspecific T cells even though they are not reactive to thesameagonist astheir targets. Instead, anisolated deletor could outcompete the target for recognition of a shared, nonstimulatory endogenous peptideMHC ligand. This mechanism was sufficient to prevent even agonist-driven autoimmune disease in a lymphopenic environment. Such a targeted regulation of homeostasis within narrow colonies of T cells with related TCR specificities for subthreshold ligands might help to prevent the loss of unrelated TCRs during multipleresponses, preserving thevaluable diversity of the repertoire.