Programmed death of autoreactive thymocytes

Abstract

T LYMPHOCYTES bearing high-affinity T-cell receptors (TCR) for self-antigens are clonally deleted during thymus development¹. Several recent studies^1,4–10have identified variable domains of the β-chain of the TCR that are specifically deleted in vivo in mouse strains that express major histocompatibility complex class II molecules in addition to poorly defined self-antigens, including those encoded by the Mls-1^a Mls-2^a loci. Deletion of autoreactive cells in these systems occurs in the thymus, and antibody blocking experiments in vivo have implicated the phenotypically immature CD4⁺CD8⁺'cortical' subset as the target population for clonal deletion^11,12. Similarly, studies with transgenic mice bearing autoreactive TCR have provided independent evidence that clonal deletion occurs at the CD4⁺CD8⁺ stage of development13. But none of these studies directly identified dying autoreactive cells, and the circumstances leading to deletion remain unclear. Here we report that neonatal thymus contains a significant popula- tion of phenotypically mature CD4⁺CD8⁻cells bearing autoreactive TCR. When placed in short-term culture, a large proportion (60%) of these autoreactive cells die selectively. Furthermore, their death can be prevented by inhibitors of macromolecule (RNA and protein) synthesis, as is the case for glucocorticoid-induced death of thymocytes^2,3. These data indicate that physiological clonal deletion of autoreactive cells involves 'programmed' cell death, and that it can occur in cells with a mature (CD4⁺CD8⁻) surface phenotype.